Tyrosine kinase inhibitors

ABSTRACT

Provided are compounds of the formula (I): or a stereoisomer, tautomer, salt, hydrate or prodrug thereof that modulate tyrosine kinase activity, compositions comprising the compounds and methods of their use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Application of PCT InternationalApplication No. PCT/US09/01691, International Filing Date Mar. 18, 2009,which claims priority of U.S. Ser. No. 61/038,032, filed Mar. 19, 2008,all of which are hereby incorporated by reference in their entirety.

FIELD

The present disclosure relates to the field of tyrosine kinase enzymeinhibition, in particular anaplastic lymphoma kinase (ALK) inhibitionusing novel small molecules. Provided are compounds capable to modulateALK activity, compositions that comprise the compounds and methods ofusing the compounds for the treatment or prevention of diseases orconditions that are characterized by ALK activity or expression.

BACKGROUND

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase thatbelongs to the insulin receptor superfamily and is normally expressed inneural tissues during embryogenesis (Morris et al., Oncogene, 1997,14:2175-2188; Iwahara et al., Oncogene, 1997, 14:439-449). Inparticular, transcripts of ALK gene are highly expressed in specificregions of the central nervous system, including the diencephalon,midbrain, and the ventral half of the spinal cord. In the peripheralnervous system, ALK expression has been detected in the trigeminal,sympathetic, and enteric ganglia. After birth, expression diminishes,but still persists in certain areas such as the olfactory bulb andthalamus. Despite the apparent function of ALK in the development of thenervous system, the physiologic role of ALK is still largely unclear.While the recent studies are proposing that pleiotrophin (PTN) andmidkine (MK) are cognate ligands for ALK (Stoica et al., J Biol Chem,2001, 276(20):16772-16779; Stoica et al., J Biol Chem, 2002,277(16):14153-14158), exact mechanisms and biological consequences ofligand-dependent ALK activation are not fully understood at this time.

ALK was initially identified because of its involvement in the humannon-Hodgkin lymphoma subtype known as anaplastic large cell lymphoma(ALCL). Many cases of ALCL are associated with a reciprocaltranslocation, t(2; 5)(p23; q35), which juxtaposes the gene at 5q35encoding nucleophosmin (NPM), a nucleolar-associated phosphoprotein,with the gene for a receptor tyrosine kinase, the anaplastic lymphomakinase (ALK), at 2p23. The resulting fusion gene encodes a chimeric80-kD protein in which 40% of the N-terminal portion of NPM is fused tothe complete intracytoplasmic portion of ALK containing the functionaltyrosine kinase domain (Morris et al., Science, 1994, 263:1281-1284).Constitutive activation of the NPM-ALK kinase domain stimulatesanti-apoptotic and mitogenic signaling pathways such as PI3K-AKT,JAK-STAT, and PLCγ, resulting in cellular transformation (Bai, 1998;Slupianek, 2001; Zamo 2002). The transforming activity of NPM/ALK isdependent on its kinase activity (Bischof 1997). While the mostfrequently occurring oncogenic ALK fusion in ALK-positive ALCL cases(“ALKomas”) is the NPM-ALK (˜80% of ALK-positive ALCL cases), other ALKgene fusions have been consequently identified in human hematologicaland solid cancers. These include TPM3-ALK (fusion of non-muscletropomyosin 3 with ALK), TPM4-ALK, ATIC-ALK, CLTC-ALK, RanBP2-ALK,TFGL/S-ALK, CARS-ALK, MSN-ALK and others.

All known ALK fusion proteins share the essential feature of having sometype of the oligomerization domain in the sequence of the ALK fusionpartner which mediates constituitive self-association of the ALK fusionthat causes constant, ligand-independent ALK kinase domain activation.Similarly to NPM-ALK, the related ALK fusion proteins have been shown topossess transforming and oncogenic potential, apparently mediated bytheir constitutive kinase activity. Although ALK-positive lymphomas havea relatively benign prognosis, about 40% of patients do not respond orrelapse after the standard therapy (CHOP). CHOP (cyclophosphamide,hydroxydoxorubicin, oncovin, prednisone) and CHOP-like multi-agentcombination chemotherapy regimens that are used for conventionaltreatment of non-Hodgkin lymphomas including ALCL are associated withconsiderable acute and chronic toxicities, a problem specificallybothersome in pediatric patients. Therefore, a highly effective andtargeted therapy would be beneficial and highly warranted not only forrelapsed patients but also as first-line therapy if well tolerated andefficacious.

In addition to ALKomas, several research groups have also described thepresence of the NPM-ALK and the related fusion proteins like CLTC-ALK ina rare form of B-cell non-Hodgkin lymphoma. Rearrangements of ALK genehave been also identified in the inflammatory fibroblastic tumors (IMT).These rare spindle cell proliferations involve malignant myofibroblastsand infiltrating non-malignant inflammatory cells in a collagenousmatrix and occur primarily in the soft tissue of children and youngadults.

More recently, a novel oncogenic ALK fusion, EML4-ALK, comprisingportions of the echinoderm microtubule-associated protein-like 4 (EML4)gene and the anaplastic lymphoma kinase (ALK) gene, has been implicatedin a subset of non-small cell lung cancer (NSCLC) (Soda, 2007). Mouse3T3 fibroblast cells forced to express this fusion tyrosine kinasegenerated transformed foci in culture and subcutaneous tumors in nudemice. The EML4-ALK fusion transcript was detected in 6.7% of the 75NSCLC patients examined; these individuals were distinct from thoseharboring mutations in the epidermal growth factor receptor gene.Presence of the oncogenic TPM4-ALK fusion was also detected byproteomics methods in esophageal cancer samples from patients in Iran(Jazii, 2006) and China (Du, 2007). These findings strongly suggest thatEML4-ALK and TPM4-ALK fusions are promising candidates for a therapeutictarget in a sizable subset of NSCLC and possibly in some esophagealcarcinomas.

Certain additional facts concerning the possible relevance ofderegulated full-length ALK signaling in some types of cancer andutility of the non-rearranged, full-length ALK as a therapeutic targetare noteworthy. The small secreted growth factors pleiotrophin (PTN) andmidkine (MK) have been shown to activate signaling of the normal,full-length ALK receptor protein (Stoica et al., 2001, supra; Stoica etal., 2002, supra). While the exact mechanism and biological significanceof ALK stimulation by the different molecular forms of these ligands arenot completely understood at this time (Lu, 2005; Perez-Pinera, 2007), afunctional connection between PTN and/or midkine and ALK is wellestablished. A large number of studies provide evidence that PTN and MKcontribute to tumor growth, abnormal tumor-associated angiogenesis andmetastasis (Kadamatsu, 2004; Bernard-Pierrot 2002). For example, bothPTN and ALK have been found to be overexpressed in human glioblastomas,and downregulation of ALK expression by ribozymes was shown to suppresshuman glioblastoma xenograft growth in mice and to prolong the survivalof the tumor-bearing animals (Powers 2002; Grzhelinsky 2005). Expressionor overexpression of the full-length ALK receptor in certainneuroblastomas, diffuse large B-cell non-Hodgkin lymphomas,leiomyosarcomas, and malignant peripheral nerve sheath sarcomas havebeen reported (Pullford et al., J Cell Physiol, 2004, 199:330-358).Similarly, it has been reported that cell lines established from commonsolid tumors of ectodermal origin, such as melanoma and breast cancer,exhibit ALK receptor mRNA expression (Pulford, 2004, supra). Additionalanalyses should elucidate the role of ALK signaling in the genesis andprogression of these various cancers aver the next few years.

Studies in which the mouse Alk gene was knocked-out demonstrate thatALK-negative mice show no evident gross anatomical, histological orfunctional abnormalities and have a normal lifespan (Pulford, 2004,supra). Therefore, the physiological functions of Alk, which is normallyexpressed primarily in neural tissues, appear to be largely redundant.These observations suggest that therapeutic approaches targeting theaberrant oncogenic functions of ALK are not likely to be associated withlimiting toxicities due to concomitant inhibition of normal ALKfunctions.

Therefore, both the various cytoplasmic ALK fusion proteins and thefull-length ALK in its transmembrane receptor form are valid moleculartargets for anticancer drugs. Consequently, a small-molecule inhibitorsof ALK kinase are likely to be a drug for suppressing of tumor growthand angiogenesis.

Recently reported preclinical studies have provided compelling proof ofprinciple for the efficacy of the inhibition of NPM-ALK in ALK-positiveALCL, with marked anti-tumor activity observed experimentally. Forinstance, studies performed by Novartis demonstrated regression ofestablished lymphoma tumors formed by subcutaneous injection of thehuman NPM-ALK-positive ALCL cell line Karpas-299 in mice when theanimals were treated with the small molecule ALK kinase inhibitorNVP-TAE684 (Galkin, 2007).

Other experimental approaches for the inhibition of oncogenic ALKsignaling have also indicated that the agents blocking this signalingare likely to possess very potent anti-cancer capabilities. Piva andcolleagues recently showed that siRNA (small inhibitory ribonucleicacid)-mediated inhibition of NPM-ALK signaling markedly diminished thedevelopment of ALCL xenografts in mice (Piva, 2006). Collectively, thesedata indicate that the inhibition of the aberrant, cancer-causingactivity of ALK fusion proteins in ALCL, as well as other ALK-drivenmalignancies, using small molecule inhibitors is very likely to producemarked anti-tumor responses.

WO 2004/063151 reported a tyrosine kinase inhibitory activity ofpyridones. Pyrroloquinixalinediones and their derivatives were shown toexhibit HIV integrase inhibitory activity (WO2004/096807).

Only a few inhibitors with activity against ALK have been reported.Sauville (Sauville et al, J. Clin. Oncol., 2001, 19, 2319-2333)disclosed a derivative of the natural product staurosporine having ananti-tumor activity in a patient with an ALK-positive anaplastic largecell lymphoma that was refractory to conventional chemo- andradio-therapy. It is important to note that the compound's ability toinhibit ALK was not tested in this study, thus, it has not been formallyproven that it is an ALK inhibitor. Indeed, a recent report suggeststhat staurosporine possesses minimal ability to directly inhibit ALK(Gunby et al., Haematologica, 2005, 90, 988-990). The naturallyoccurring, structurally related benzoquinone analogues, geldanamycin and17-allylamino-17-demethoxygeldanamycin (Bonvini et al., Cancer. Res.2002, 62, 1559-1566) and herbimycin A (Turturro et al., Clin. CancerRes. 2002, 8, 240-245) have been reported to exert ALK inhibition viaheat shock protein pathways, enhancing the proteasome-mediateddegradation of the ALK protein. Most recently, a series ofpyrazolo[3,4-c]isoquinoline derivatives with ALK-inhibitory activity waspublished in WO 2005009389.

One of the challenges of developing an ATP-competitive small-moleculeALK inhibitor is to provide sufficient selectivity of the compound forALK versus inhibition of other structurally related protein kinases. Dueto the existence of about 520 evolutionary related protein kinases inthe human genome, this could be a demanding task. In particular,inhibition of the insulin receptor kinase which is closely structurallyrelated to ALK is highly undesirable due to the risk of blocking insulinaction and the resultant hyperglycemia.

Another highly related RTK is Insulin-Like Growth Factor Receptor I(IGF1R). In the recent years, IGF1R emerged as an attractive oncologytarget in a broad variety of malignancies (Riedman and Macaulay, 2006;Tao et al 2007). However, suppression of IGF1R signaling may potentiallyhave undesirable side-effects in a clinical context where normalcell/tissue proliferation and development are essential, such astreating pediatric patients (ALCL). Therefore, a sufficiently highselectivity of ALK inhibition versus inhibition of such related RTKs asInsulin Receptor and IGF is likely to be a desirable trait in a clinicalALK inhibitor. Conversely, inhibition of a small subset oftherapeutically relevant PTKs (multitargeting), in addition to ALK, canimprove the efficacy of an oncology drug, especially for solid tumorswhich are often heterogeneous and have complicated tumor biology.

Another group of tyrosine kinases evolutionary and structurally relatedto ALK is Ret, Ros, Axl and kinases that are members of Trk family (TrkA, B and C).

RET is a receptor tyrosine kinase that has a role in transducing growthand differentiation signals in tissues derived from the neural crest andis required for normal development of the sympathetic, parasympatheticand enteric nervous systems and the kidney. Gain of function mutationsof Ret are associated with the development of several types of humancancers, including medullar thyroid carcinoma and multiple endocrineneoplasias type II and III (or MEN2A and MEN2B). RET mutations have beenalso identified in a small percentage of pheochromocytomas. Chromosomalrearrangements involving the RET gene are one of the most common causesof a sporadic form of thyroid cancer called papillary thyroid carcinoma(also known as RET/PTC). There is a compelling experimental evidencethat thyroid cell transformation to PTC is driven by hyperactivated Ret(Santoro, 2004]. Kinase inhibitors with activity against RET arecurrently in preclinical or clinical development for these types ofcancers.

ROS is a receptor tyrosine kinase that has been found to beconstitutively activated in a subset of glioblastomas as a result ofgenomic translocations (Charest, 2003; Charest, 2006) and may representan emerging therapeutic target in this highly malignant and deadly braintumor.

AXL is a unique tyrosine kinase receptor, implicated in the inhibitionof apoptosis as well as promoting neovascularization, and it is emergingas a viable therapeutic target in a number of malignancies, both solidand hematologic (Holland, 2005). In particular, it is a chronicmyelogenous leukemia-associated oncogene (O'Bryan, 1991; Jannsen, 1991)and is also associated with colon, prostate cancer and melanoma (VanGinkel, 2004; Sainaghi, 2005). Overexpression of Axl in myeloid cellshas been shown to be involved in Type II diabetes (Augustine, 1999).Modulation of Axl activity by small-molecule kinase inhibitors may haveutility in therapy of the disease states mentioned above.

TrkA is a receptor tyrosine kinase that belongs to a subfamily oftyrosine kinases that also includes TrkB, and TrkC. TrkB and TrkC arestructurally closely related to TrkA, but respond to different ligandsin the neurotrophin (NT) family. Nerve growth factor (NGF) signalingthrough TrkA has been well characterized and is similar to signaltransduction mechanisms of other tyrosine kinase receptors. As outlinedin more detail below, TrkA is a well validated or a potential drugtarget in a variety of malignancies as well as in neuropathic pain andcertain inflammatory diseases. The roles of the two other members of theneurothropin receptor TK family, TrkB and TrkC, in disease states hasreceived less attention, however the emerging evidence implicates bothof them in several types of neoplasias.

TrkA gene was originally described as a chimeric oncogene in coloncancer (Martin-Zanca, 1986] and its activating genomic translocationsare common in papillary thyroid carcinomas (Bongarzone, 1989; Pierotti,2006) and occur in breast cancer as well (Brzezianska, 2007).Hyperactivating deletion or fusion mutations of TrkA and TrkC were alsoidentified in some acute myeloid leukemias as well as solid tumors(Reuther, 2000; Eguchi, 2005).

Overexpression of TrkA in malignant versus normal tissues andassociation with poor prognosis was shown in prostate, pancreaticcancers, melanomas, mesotheliomas (Festuccia, 2007; Myknyoczki, 1999;Florenes, 2004; Davidson, 2004). TrkA is overexpressed in the majorityof prostate carcinomas, and is further increased in androgen-independenttumors (Papatsoris, 2007). In prostatic carcinomas, an autocrine loopinvolving NGF and TrkA is responsible for tumor progression (Djakiew,1993). An autocrine NGF/TrkA loop and mitogenic role of NGF has beendemonstrated in breast cancer cells as well (Chiarenza, 2001l; Dolle,2003). It has also been shown that NGF signaling hasangiogenesis-promoting effect (Cantarella, 2002).

TrkB, sometimes in conjunction with its ligand BDNF, is oftenoverexpressed in a variety of human cancers, ranging from neuroblastomasto pancreatic ductal adenocarcinomas, in which it may allow tumorexpansion and contribute to resistance to anti-tumor agents. TrkB actsas a potent suppressor of anoikis (detachment-induced apoptosis), whichis associated with the acquisition of an aggressive tumorigenic andmetastatic phenotype in vivo (Desmet, 2006; Douma, 2004). In summary,Trk family members have been implicated as oncogenes in a number ofneoplasms including prostate, thyroid, pancreatic, colon, breast,ovarian cancers, melanomas and some leukemias. For prostate cancer andthyroid carcinomas, TrkA is especially well validated as a drug target.

Strong and diverse experimental evidence suggests that nerve growthfactor (NGF), signaling through TrkA pathway, is a mediator of somepersistent pain states, including neuropathic and inflammatory pain(Pezet, 2006; Hefti, 2006; Bennet, 2001). Function-neutralizing anti-NGFand anti-TrkA antibodies demonstrated therapeutic effect in models ofinflammatory, neuropathic, skeletal and cancer pain (Ugolini, 2007;Koewler, 2007; Sevcik, 2005). In such disease states as prostate cancerwith metastatic bone pain and pancreatic cancer with perineuralinvasion, cancer progression, pain and TrkA signaling has been shown tobe all positively correlated (Dang, 2006; Halvorson, 2005). Inhibitionof the NGF/TrkA pathway appears to be very well validated for treatmentof chronic pain of different natures: (i) inflammatory pain; (ii)neuropathic pain and (iii) cancer pain.

It is noteworthy that in the skin, TrkA receptor mediates the ability ofNGF to stimulate keratinocytes proliferation and inhibit keratinocytesapoptosis. NGF is produced by keratinocytes to stimulate their cellproliferation with an autocrine loop and melanocyte proliferation with aparacrine pathway (Di Marco, 1993; Pincelli, 2000). NGF/TrkA signalingalso modulates inflammation (Frossard, 2004) and proliferation ofterminal cutaneous nerves (Raychaudhury, 2004), components of psoriasisand atopic dermatitis. Murine models for psoriasis and atopic dermatitishave been established and K252a and AG879, both potent non-clinical TrkAinhibitors, were demonstrated to have therapeutic effect [Raychaudhury,2004) Takano, 2007) in the models. This data indicates that TrkA is apotential drug target in skin disorders characterized by keratinocyteshyperproliferation.

Thus, blocking the ALK activity represents a rational, targeted approachto therapy of various diseases. As there are several tyrosine kinasesthat are evolutionary and structurally related to ALK, such as Ret, Ros,Axl and members of Trk family, there is an opportunity to eitheridentify a multitargeted kinase inhibitor with a potential utility inother types of malignancies not targeted by selective ALK inhibition, orto fine-tune the inhibition selectivity towards a particular kinase ofinterest by lead optimization.

SUMMARY

Provided herein are selective ALK activity inhibitors, compositions thatcomprise the compounds and methods of using the compounds for thetreatment or prevention of diseases or conditions that are characterizedby ALK activity or expression in mammals.

Provided herein are selective inhibitors of tyrosine kinasesevolutionary and structurally related to ALK, such as Ret, Ros, Axl andmembers of Trk family (Trk A, B and C) and are useful for the treatmentor prevention of diseases or conditions characterized by aberrant ALK,RET, ROS, Axl and Trk family of tyrosine kinase activity or expressionin mammals.

The compounds provided herein are selective inhibitors of ALK, RET, ROS,Axl and Trk family of tyrosine kinases as compared to the inhibitoryactivity of one or more other tyrosine kinases such as IRK (InsulinReceptor Kinase) or IGF1R.

The compounds provided herein can be used to treat and/or prevent amammal affected by a neoplastic disease, in particular ALK-positiveanaplastic large cell lymphoma, inflammatory myofibroblastic tumors,diffuse large B-cell non-Hodgkin lymphoma, non-small cell lung cancer,esophageal carcinoma, breast cancer, neuroblastoma and glioblastoma.

Certain compounds provided herein have therapeutic utility in treatingvarious types of neoplasms and other disease states, caused by theaberrant activity of Alk, RET, ROS, AXL and TRK family tyrosine kinases.In particular, provided compounds potently inhibit the catalyticactivity of TrkA and/or other Trk family kinases and thereby provide newtreatment strategies for patients afflicted with cancer, chronic painand certain hyperproliferative skin diseases.

The compounds provided herein can be used to treat and/or prevent amammal affected by tyrosine kinase related disorder such as cancerselected from, but not limited to, astrocytoma, basal or squamous cellcarcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer,colorectal cancer, chrondrosarcoma, cervical cancer, adrenal cancer,choriocarcinoma, esophageal cancer, endometrial carcinoma,erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neckcancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma,melanoma, non-small cell lung cancer, neural cancer, ovarian cancer,pancreatic cancer, prostate cancer, renal cell carcinoma,rhabdomyosarcoma, small cell lung cancer, thyoma, thyroid cancer,testicular cancer and osteosarcoma.

The compounds provided herein can be used to treat and/or prevent amammal affected by tyrosine kinase related disorder such ashyperproliferative skin disease selected from, but not limited to,psoriasis, acne vulgaris, acne rosacea, actinic keratosis, solarkeratosis, Bowen's disease, ichthyosis, hyperkeratosis, disorders ofkeratinization such as Darrier's disease, palmoplanter keratoderma,pityriasis rubra pilaris, epidermal naevoid syndrome, erythrokeratodermavariabilis, epidermolytic hyperkeratosis, non-bullous ichthyosiformerythroderma, cutaneous lupus erythematosus and lichen planus.

In one aspect, provided are compounds of the formula (I) or astereoisomer, tautomer, salt, hydrate or prodrug thereof:

wherein:

R² and R³ are each independently hydrogen, lower alkyl, lower alkoxy,halogen, cyano, lower alkylamino or di-lower alkylamino;

W is O, S, or NR^(e), wherein

-   -   R^(e) is selected from hydrogen or lower alkyl;

or W represents bonding of two hydrogen atoms to a carbon atom, formingan optionally substituted methylene group:

wherein

R^(f) is selected from hydrogen or lower alkyl;

R⁴ is

wherein

-   -   R^(a) is optionally substituted aryl or heteroaryl;    -   R^(b) is lower alkyl, trifluoromethyl, hydroxymethyl,        methoxymethyl, aminomethyl, di-lower alkylaminomethyl or        heterocyclylaminomethyl;    -   R^(c) is selected from hydrogen, hydroxy, lower alkoxy, or lower        alkyl;    -   R^(d) is selected from hydrogen, or lower alkyl; and

R¹ is as described below.

In another aspect, provided are compounds of the formula (I) that areALK inhibitors, selective especially with respect to IGF1R and/or IRK.

In yet another aspect, provided are pharmaceutical compositionscomprising one or more compounds of the formula (I) or a stereoisomer,tautomer, salt, hydrate or prodrug thereof useful for treatment of adisease or condition characterized by Alk activity or expression.

In yet another aspect, provided are pharmaceutical compositionscomprising one or more compounds of the formula (I) or a stereoisomer,tautomer, salt, hydrate or prodrug thereof useful for treatment of adisease or condition characterized by Alk, RET, ROS, AXL and TRK familytyrosine kinases activity or expression.

A disease or condition characterized by ALK activity or expressionincludes but is not limited to ALK-positive anaplastic large celllymphoma, an inflammatory myofibroblastic tumor, diffuse large B-cellnon-Hodgkin lymphoma, non-small cell lung cancer, esophageal carcinoma,breast cancer, neuroblastoma and glioblastoma.

A disease or condition characterized by ALK, RET, ROS, AXL and TRKfamily tyrosine kinases activity or expression includes but is notlimited to cancer, chronic pain and certain hyperproliferative skindiseases.

In yet another aspect, provided are methods for treating a disease ordisorder characterized by ALK activity or expression comprisingadministration to mammal one or more compounds of the formula (I).

In yet another aspect, provided are methods for treating a disease ordisorder characterized by ALK, RET, ROS, AXL and TRK family tyrosinekinases activity or expression comprising administration to mammal oneor more compounds of the formula (I).

DETAILED DESCRIPTION

Definitions

When describing the compounds, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, thefollowing terms have the following meanings unless otherwise indicated.When two terms referring to chemical groups are combined, the combinedterm refers to the groups covalently linked in either orientation,unless specified otherwise. For instance, the term “acylamino” can referto either “—C(O)—N(R)—” or to “—N(R)—C(O)—” unless specified otherwiseand similarly sulfonamido or aminosulfonyl can refer to either—S(O₂)—N(R)— or —N(R)—S(O₂)—.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Aliphatic” refers to hydrocarbyl organic compounds or groupscharacterized by a straight, branched or cyclic arrangement of theconstituent carbon atoms and an absence of aromatic unsaturation.Aliphatics include, without limitation, alkyl, alkylene, alkenyl,alkenylene, alkynyl and alkynylene. Aliphatic groups typically have from1 or 2 to about 12 carbon atoms.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups, inone embodiment having up to about 11 carbon atoms, in anotherembodiment, as a lower alkyl, from 1 to 8 carbon atoms, and in yetanother embodiment, from 1 to 6 carbon atoms. The hydrocarbon chain maybe either straight-chained or branched. This term is exemplified bygroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term “loweralkyl” refers to alkyl groups having 1 to 6 carbon atoms. The term“alkyl” also includes “cycloalkyl” as defined below.

“Substituted alkyl” includes those groups recited in the definition of“substituted” herein, and in one embodiment refers to an alkyl grouphaving 1 or more substituents, in another embodiment, from 1 to 5substituents, and yet in another embodiment, from 1 to 3 substituents,selected from the group consisting of acyl, acylamino, acyloxy, alkoxy,substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy,aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substitutedcycloalkyl, halogen, hydroxyl, heteroaryl, keto, nitro, alkylthio,substituted alkylthio, arylthio, thioketo, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂—, and aryl-S(O)₂—.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groups inone embodiment having up to about 11 carbon atoms and in anotherembodiment having 1 to 6 carbon atoms which can be straight-chained orbranched. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—) and the like.

“Substituted alkylene” includes those groups recited in the definitionof “substituted” herein, and particularly refers to an alkylene grouphaving in one embodiment 1 or more substituents, in another embodimentfrom 1 to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, halogen, hydroxyl, keto, nitro, alkylthio, substituted alkylthio,arylthio, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— andaryl-S(O)₂—.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbylgroups having in one embodiment up to about 11 carbon atoms, in anotherembodiment from 2 to 8 carbon atoms, and in yet another embodiment from2 to 6 carbon atoms, which can be straight-chained or branched andhaving at least 1 and particularly from 1 to 2 sites of olefinicunsaturation. Particular alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), isopropenyl (—C(CH3)=CH2), vinyl andsubstituted vinyl, and the like.

“Substituted alkenyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkenyl group havingin one embodiment 1 or more substituents, in another embodiment from 1to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbylgroups particularly having in one embodiment up to about 11 carbon atomsand in another embodiment 2 to 6 carbon atoms which can bestraight-chained or branched and having at least 1 and particularly from1 to 2 sites of olefinic unsaturation. This term is exemplified bygroups such as ethenylene (—CH═CH—), the propenylene isomers (e.g.,—CH═CHCH₂— and —C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to acetylenically unsaturated hydrocarbyl groupsparticularly having in one embodiment up to about 11 carbon atoms and inanother embodiment 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofalkynyl unsaturation. Particular non-limiting examples of alkynyl groupsinclude acetylenic, ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Substituted alkynyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkynyl group havingin one embodiment 1 or more substituents, in another embodiment from 1to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkanoyl” as used herein, which can include “acyl”, refers to the groupR—C(O)—, where R is hydrogen or alkyl as defined above.

“Alkoxy” refers to the group —OR where R is alkyl. Particular alkoxygroups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkoxy group havingin one embodiment 1 or more substituents, in another embodiment from 1to 5 substituents, and yet in another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl,hydroxyl, keto, nitro, alkylthio, substituted alkylthio, arylthio,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Heteroalkyl” refers to an alkyl chain as specified above, having one ormore heteroatoms selected from O, S, or N.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as indacene, sindacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta 2,4 diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Particularly, anaryl group comprises from 6 to 14 carbon atoms.

“Substituted Aryl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an aryl group that mayoptionally be substituted in one embodiment with 1 or more substituents,in another embodiment from 1 to 5 substituents, and in yet anotherembodiment from 1 to 3 substituents, selected from the group consistingof acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl,substituted alkynyl, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro,alkylthio, substituted alkylthio, arylthio, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring. In certainembodiments, a bicyclic compound provided herein comprises a fused aryl.

“Amino” refers to the radical —NH₂.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R)₂ whereeach R is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, and whereboth R groups are joined to form an alkylene group. When both R groupsare hydrogen, —N(R)₂ is an amino group.

“Azido” refers to the radical —N₃.

“Carbamoyl” refers to the radical —C(O)N(R)₂ where each R group isindependently hydrogen, alkyl, cycloalkyl or aryl, as defined herein,which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like.

“Substituted cycloalkyl” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a cycloalkyl grouphaving in one embodiment 1 or more substituents, in another embodimentfrom 1 to 5 substituents, and in yet another embodiment from 1 to 3substituents, selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Cycloalkoxy” refers to the group —OR where R is cycloalkyl. Suchcycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxyand the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Substituted cycloalkenyl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to acycloalkenyl group having in one embodiment 1 or more substituents, inanother embodiment from 1 to 5 substituents, and in yet anotherembodiment from 1 to 3 substituents, selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, alkylthio, substituted alkylthio, arylthio, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo. Particularhalo groups are either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” or “heteroaromatic” refers to a monovalent heteroaromaticgroup derived by the removal of one hydrogen atom from a single atom ofa parent heteroaromatic ring system. Typical heteroaryl groups include,but are not limited to, groups derived from acridine, arsindole,carbazole, □-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, tetrahydroisoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, tetrahydroquinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. Particularly, heteroaryl can includeother saturated ring systems, and can therefore be derived fromindoline, indolizine, tetrahydroquinoline, and tetrahydroisoquinoline.In certain embodiments, the heteroaryl group is between 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being useful in certainembodiments. Particular heteroaryl groups are those derived fromthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,pyrimidine, quinoline, tetrahydroquinoline, isoquinoline,tetrahydroisoquinoline, imidazole, oxazole and pyrazine.

As used herein, the term “cycloheteroalkyl” refers to a stableheterocyclic non-aromatic ring and fused rings containing one or moreheteroatoms independently selected from N, O and S. A fused heterocyclicring system may include carbocyclic rings and need only include oneheterocyclic ring. Examples of heterocyclic rings include, but are notlimited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl.

“Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to aradical such as RS— wherein R is any substituent described herein. Incertain embodiments, “substituted sulfanyl” refers to a radical —SRwhere R is an alkyl or cycloalkyl group as defined herein that may beoptionally substituted as defined herein. Alkylthio or arylthio refer tothe above sulfanyl group. Representative examples include, but are notlimited to, methylthio; ethylthio, propylthio, butylthio, phenylthio andthe like.

“Sulfinyl” refers to the radical —S(O)H. “Substituted sulfinyl” refersto a radical such as S(O)—R wherein R is any substituent describedherein.

“Sulfonyl” refers to the divalent radical —S(O2)-. “Substitutedsulfonyl” refers to a radical such as —S(O₂)—R wherein R is anysubstituent described herein. “Aminosulfonyl” or “Sulfonamide” refers tothe radical H₂N(O-2)S—, and “substituted aminosulfonyl” “substitutedsulfonamide” refers to a radical such as R2N(O-2)S— wherein each R isindependently any substituent described herein. In particularembodiments, R is selected from H, lower alkyl, alkyl, aryl andheteroaryl.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms as long as the heteroaromatic ring is chemically feasibleand stable.

“Pharmaceutically acceptable salt” refers to any salt of a compoundprovided herein which retains its biological properties and which is nottoxic or otherwise undesirable for pharmaceutical use. Such salts may bederived from a variety of organic and inorganic counter-ions well knownin the art and include. Such salts include: (1) acid addition saltsformed with organic or inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic,trifluoroacetic, trichloroacetic, propionic, hexanoic,cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic,succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric,benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic,phthalic, lauric, methanesulfonic, ethanesulfonic,1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic,4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic,camphoric, camphorsulfonic,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic,3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric,gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic,cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2)salts formed when an acidic proton present in the parent compound either(a) is replaced by a metal ion, e.g., an alkali metal ion, an alkalineearth ion or an aluminum ion, or alkali metal or alkaline earth metalhydroxides, such as sodium, potassium, calcium, magnesium, aluminum,lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with anorganic base, such as aliphatic, alicyclic, or aromatic organic amines,such as ammonia, methylamine, dimethylamine, diethylamine, picoline,ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylene-diamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like.

Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium and the like, and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, besylate, acetate, maleate, oxalate and the like. The term“physiologically acceptable cation” refers to a non-toxic,physiologically acceptable cationic counterion of an acidic functionalgroup. Such cations are exemplified by sodium, potassium, calcium,magnesium, ammonium and tetraalkylammonium cations and the like.

“Solvate” refers to a compound provided herein or a salt thereof, thatfurther includes a stoichiometric or non-stoichiometric amount ofsolvent bound by non-covalent intermolecular forces. Where the solventis water, the solvate is a hydrate.

It is to be understood that compounds having the same molecular formulabut differing in the nature or sequence of bonding of their atoms or inthe arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, when it is bonded to four different groups, a pairof enantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is designated (R) or(S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew.Chem. 78:413-447, Angew. Chem., Int. Ed. Engl. 5:385-414 (errata: Angew.Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem.94:614-631, Angew. Chem. Internat. Ed. Eng. 21:567-583; Mata and Lobo,1993, Tetrahedron: Asymmetry 4:657-668) or can be characterized by themanner in which the molecule rotates the plane of polarized light and isdesignated dextrorotatory or levorotatory (i.e., as (+)- or (−)-isomers,respectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of enantiomers is called a “racemic mixture”.

In certain embodiments, the compounds provided herein may possess one ormore asymmetric centers; such compounds can therefore be produced as theindividual (R)- or (S)-enantiomer or as a mixture thereof. Unlessindicated otherwise, for example by designation of stereochemistry atany position of a formula, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof.Methods for determination of stereochemistry and separation ofstereoisomers are well-known in the art. In particular embodiments,provided are the stereoisomers of the compounds depicted herein upon useof stereoisomerically pure intermediates in their synthesis, such aspure enantiomers, or diastereomers as building blocks, prepared bychiral synthesis methodologies, or resolution by formation ofdiastereomeric salts with chiral acid or base and their separation, orseparation by means of chromatography, including using chiral stationaryphase. The racemic, or diastereomeric mixtures of compounds providedherein can also be separated by means of chromatography, includingchiral stationary phase chromatography.

In certain embodiments, the compounds provided herein are“stereochemically pure.” A stereochemically pure compound has a level ofstereochemical purity that would be recognized as “pure” by those ofskill in the art. Of course, this level of purity will be less than100%. In certain embodiments, “stereochemically pure” designates acompound that is substantially free of alternate isomers. In particularembodiments, the compound is 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, 99.5% or 99.9% free of other isomers.

As used herein, the terms “disorder” and “disease” are usedinterchangeably to refer to a condition in a subject. Certain conditionsmay be characterized as more than one disorder. For example, certainconditions may be characterized as both non-cancerous proliferativedisorders and inflammatory disorders.

As used herein, the term “effective amount” refers to the amount of acompound provided herein which is sufficient to reduce or ameliorate theseverity, duration of a disorder, cause regression of a disorder,prevent the recurrence, development, or onset of one or more symptomsassociated with a disorder, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy.

As used herein, the term “in combination” refers to the use of more thanone therapies. The use of the term “in combination” does not restrictthe order in which therapies (e.g., prophylactic and/or therapeuticagents) are administered to a subject with a disorder. A first therapycan be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes,45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapy to a subject witha disorder.

As used herein, the terms “prophylactic agent” and “prophylactic agents”as used refer to any agent(s) which can be used to prevent disorder orone or more symptoms thereof. In certain embodiments, the term“prophylactic agent” refers to a compound provided herein. In certainother embodiments, the term “prophylactic agent” does not refer acompound provided herein. In certain embodiments, a prophylactic agentis an agent which is known to be useful for, or has been or is currentlybeing used to the prevent or impede the onset, development, progressionand/or severity of a disorder. Prophylactic agents may be characterizedas different agents based upon one or more effects that the agents havein vitro and/or in vivo. For example, an anti-angiogenic agent may alsobe characterized as an immunomodulatory agent.

As used herein, the terms “prevent,” “preventing” and “prevention” referto the prevention of the recurrence, onset, or development of one ormore symptoms of a disorder in a subject resulting from theadministration of a therapy, or the administration of a combination oftherapies.

As used herein, the phrase “prophylactically effective amount” refers tothe amount of a therapy which is sufficient to result in the preventionof the development, recurrence or onset of one or more symptomsassociated with a disorder, or to enhance or improve the prophylacticeffect(s) of another therapy.

As used herein, the terms “subject” and “patient” are usedinterchangeably herein. The terms “subject” and “subjects” refer to ananimal, in certain embodiments a mammal including a non-primate (e.g., acow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkeysuch as a cynomolgous monkey, a chimpanzee and a human), and moreparticularly a human. In another embodiment, the subject is a farmanimal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or acat). In certain embodiments, the subject is a human.

As used herein, the term “synergistic” refers to a combination of acompound provided herein and another therapy which has been or iscurrently being used to prevent, manage or treat a disorder, which ismore effective than the additive effects of the therapies. A synergisticeffect of a combination of therapies permits the use of lower dosages ofone or more of the therapies and/or less frequent administration of saidtherapies to a subject with a disorder. The ability to utilize lowerdosages of a therapy and/or to administer said therapy less frequentlyreduces the toxicity associated with the administration of said therapyto a subject without reducing the efficacy of said therapy in theprevention, management or treatment of a disorder. In addition, asynergistic effect can result in improved efficacy of agents in theprevention, management or treatment of a disorder. Finally, asynergistic effect of a combination of therapies may avoid or reduceadverse or unwanted side effects associated with the use of eithertherapy alone.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment, management, oramelioration of a disorder or one or more symptoms thereof. In certainembodiments, the term “therapeutic agent” refers to a compound providedherein. In certain other embodiments, the term “therapeutic agent” doesnot refer to a compound provided herein. In certain embodiments, atherapeutic agent is an agent which is known to be useful for, or hasbeen or is currently being used for the treatment, management,prevention, or amelioration a disorder or one or more symptoms thereof.Therapeutic agents may be characterized as different agents based uponone or more effects the agents have in vivo and/or in vitro, forexample, an anti-inflammatory agent may also be characterized as animmunomodulatory agent.

As used herein, the term “therapeutically effective amount” refers tothat amount of a therapy sufficient to result in the amelioration of oneor more symptoms of a disorder, prevent advancement of a disorder, causeregression of a disorder, or to enhance or improve the therapeuticeffect(s) of another therapy. In a specific embodiment, with respect tothe treatment of cancer, an effective amount refers to the amount of atherapy that inhibits or reduces the proliferation of cancerous cells,inhibits or reduces the spread of tumor cells (metastasis), inhibits orreduces the onset, development or progression of one or more symptomsassociated with cancer, or reduces the size of a tumor. In certainembodiments, a therapeutically effective of a therapy reduces theproliferation of cancerous cells or the size of a tumor by at least 5%,at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or at least 99%, relative to acontrol or placebo such as phosphate buffered saline (“PBS”).

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of a disorder or oneor more symptoms thereof. In certain embodiments, the terms “therapy”and “therapies” refer to chemotherapy, radiation therapy, hormonaltherapy, biological therapy, and/or other therapies useful in theprevention, management, treatment or amelioration of a disorder or oneor more symptoms thereof known to one of skill in the art (e.g., skilledmedical personnel).

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a disorder, or the amelioration of one or more symptomsthereof resulting from the administration of one or more therapies.

As used herein, the term “modulation” or “modulating” refers to thealteration of the catalytic activity of a tyrosine kinase. Inparticular, modulating can refer to the activation or to the inhibitionof the tyrosine kinase. The tyrosine kinase can be any tyrosine kinaseknown to those of skill in the art. In certain embodiments, the tyrosinekinase is a receptor tyrosine kinase or an intracellular tyrosinekinase.

As used herein, the term “ALK” refers to anaplastic lymphoma kinase.

The definitions used herein are according to those generally accepted inthe pertinent art and those specified herein.

Compounds

In one embodiment, provided are compounds of the formula (I) or astereoisomer, tautomer, salt, hydrate or prodrug thereof:

wherein:

R² and R³ are each independently hydrogen, lower alkyl, lower alkoxy,halogen, cyano, amino, lower alkylamino, or di-lower alkylamino;

W is O, S, or NR^(e), wherein

-   -   R^(e) is selected from hydrogen or lower alkyl;

or W represents bonding of two hydrogen atoms to a carbon atom, formingan optionally substituted methylene group:

-   -   wherein R^(f) is selected from hydrogen or lower alkyl;

R⁴ is

wherein

-   -   R^(a) is optionally substituted aryl or heteroaryl,    -   R^(b) is lower alkyl, trifluoromethyl, hydroxymethyl,        methoxymethyl, aminomethyl, lower alkylaminomethyl, di-lower        alkylaminomethyl or heterocyclylaminomethyl;    -   R^(c) is selected from hydrogen, hydroxy, lower alkoxy, or lower        alkyl;    -   R^(d) is selected from hydrogen, or lower alkyl; and

R¹ is independently selected from optionally substituted heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, heterocyclyloxyalkyl,heteroalkyl, heterocyclylaminoalkyl, aminoalkyl, lower alkylaminoalkyl,di-(lower alkyl)-aminoalkyl, aminocycloalkyl, alkylaminocycloalkyl,di-(lower alkyl)-aminocycloalkyl, di-(lower alkyl)-aminocycloalkylalkyl,wherein the substituents are selected from hydrogen, lower alkyl,hydroxy, lower alkoxy, amino, amidino, carboxamido, sulfonamido,hydroxy, cyano, primary, secondary or tertiary amino, halo, azido, loweralkoxyalkyl, cyanoalkyl, azidoalkyl, haloalkyl, hydroxyalkyl,methanesulfonylalkyl, primary, secondary or tertiary amino-alkyl,optionally substituted aryl, heteroaryl, heteroalkyl, heterocyclyl,cycloalkyl, alkenyl and alkynyl.

In another embodiment, R² and R³ are hydrogen or methyl.

In yet another embodiment, W is

In one embodiment, R^(a) is optionally substituted thienyl or phenylwherein the optional substituents are alkyl, alkoxy or halo.

In another embodiment, R^(a) is optionally substituted thienyl or phenylwherein the optional substituents are methyl, methoxy or fluoro.

In yet another embodiment, R^(a) is thiophen, phenyl, methylthiophen,methylphenyl, fluoromethylphenyl, fluoromethoxyphenyl, trifluorophenylor tetrafluorophenyl.

In another embodiment, R^(c) and R^(d) are hydrogen or hydroxy.

In one embodiment, R^(b) is alkyl.

In another embodiment, R^(b) is methyl.

In another embodiment, R¹ includes, but is not limited to:

wherein:

R¹³ is selected from hydrogen, lower alkyl, heteroalkyl, heterocyclyl,cycloalkyl and heterocycloalkyl;

R¹⁴ is selected from hydrogen, hydroxy, lower alkoxy, di-(loweralkyl)amino, lower alkyl, heteroalkyl, heterocyclyl, cycloalkyl,heterocycloalkyl, lower alkoxyalkyl, cyanoalkyl, azidoalkyl, nitroalkyl,ketoalkyl, methanesulfonylalkyl, aminoalkyl, lower alkylaminoalkyl,di-(lower alkyl)aminoalkyl, optionally substituted aryl, heteroaryl,arylalkyl, and heteroarylalkyl;

R¹⁵ is selected from hydrogen, amino, lower alkylamino, di-(loweralkyl)amino, hydroxy, lower alkoxy, heteroalkyl, lower alkoxyalkyl,aminoalkyl, lower alkylaminoalkyl and di-(lower alkyl)aminoalkyl;

a is an integer from 0 to 4; and

t, u, v are independent integers from 0 to 5.

It is understood that if any of the integers is (are) 0 (zero), it meansa covalent chemical bond.

In another embodiment, R¹ is further selected from:

In certain embodiments, one or more of the R¹ methylene chain betweenthe connection and the heteroatom is optionally substituted by one ormore hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy,carboxamido or sulfonamido.

In certain embodiments, the R¹ methylene groups is optionallysubstituted by a heteroatom selected from O and S, or NR***, S═O, orS(═O)₂, wherein R*** is selected from hydrogen, hydroxy, lower alkyl,lower alkoxy, heteroalkyl, hydroxyalkyl, aminoalkyl, loweralkylaminoalkyl and di-(lower alkyl)aminoalkyl.

In certain embodiments, any R¹ ring is optionally substituted by a loweralkyl or heteroalkyl group.

In another embodiment, provided are compounds of the formula (Ia) or astereoisomer, tautomer, salt, hydrate or prodrug thereof:

wherein the substituents are as defined above.

The compounds provided herein are selective ALK inhibitors, especiallycompared to IGF1R and/or IR (insulin receptor) inhibition.

The following exemplary compounds according to formula (I) were preparedaccording to the methods described herein:

All compounds include tautomeric forms, as exemplified by, but notlimited to the following:

Included are also without limitation their corresponding prodrugs, suchas are known in the art. They include esters, such as acetate,propionate and other esters of fatty acids, aminoacids natural andunnatural, such as glycine, valine esters and the like, amides such asacetamides, propionamides and other amides of fatty or aromatic acids,aminoacids, such as glycinamide and other aminonoacids natural orunnatural, ethers, such as methoxy or ethoxy, methoxyethyl, ethoxyethyl,hydroxyethyl, propyleneglycol ethers and/or polyethyleneglycol ethersand/or polypropylene glycol ethers.

Methods of Use

In one aspect, provided are methods for modulating the activity of atyrosine kinase. In one embodiment, the methods comprise the step ofcontacting the tyrosine kinase with a compound provided herein. Thecontacting can be in any environ known to those of skill in the art, forinstance, in vitro, in vivo, ex vivo or otherwise. In certainembodiments, provided are methods of modulating the activity of atyrosine kinase in a mammal in need thereof comprising contacting thetyrosine kinase with a compound provided herein. Modulating can refer tothe activation or to the inhibition of the tyrosine kinase. The tyrosinekinase can be any tyrosine kinase known to those of skill in the art. Incertain embodiments, the tyrosine kinase is a receptor tyrosine kinaseor an intracellular tyrosine kinase.

In certain embodiments, the receptor tyrosine kinase is selected fromthe group consisting of EGFR, HBER2, HER3, HER4, IR, IGF1R, IRR, PDGFRα,PDGFRβ, TrkA, TrkB, TrkC, HGFR, CSFIR, C-Kit, C-fms, Flk4, KDR/Flk-1,Flt-1, FGF1R, FGF2R, FGF3R and FGF4R.

In certain embodiments, the intracellular tyrosine kinase is selectedfrom the group consisting of Alk, Src, Frk, Btk, Csk, Abl, ZAP70, Fes,Fps, Fak, Jak1, Jak2, Jak3, Jak4, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgrand Yrk.

In specific embodiments, the intracellular tyrosine kinase is Alk.

In another specific embodiment, the tyrosine kinases are those that areevolutionary and structurally related to ALK, such as Ret, Ros, Axl andmembers of Trk family (Trk A, B and C).

In another aspect, provided are methods for treating or preventing atyrosine kinase related disorder in a subject in need thereof. In oneembodiment, the methods comprise administering to the subject an amountof a disclosed compound effective to treat or prevent the disorder. Thecompound can be in the form of a pharmaceutical composition or a unitdose as described below.

A tyrosine kinase related disorder can be any disorder known to those ofskill in the art to be related to tyrosine kinase activity. Suchdisorders include those related to excessive tyrosine kinase activity,those related to reduced tyrosine kinase activity and to those that canbe treated or prevented by modulation of tyrosine kinase activity.Excessive tyrosine kinase activity can arise as the result of, forexample: (1) tyrosine kinase expression in cells which normally do notexpress tyrosine kinases; (2) increased tyrosine kinase expressionleading to unwanted cell proliferation, differentiation and/or growth;or, (3) decreased tyrosine kinase expression leading to unwantedreductions in cell proliferation, differentiation and/or growth.

The tyrosine kinase related disorder can be a cancer selected from, butnot limited to, astrocytoma, basal or squamous cell carcinoma, braincancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer,chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma,esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing'ssarcoma, gastrointestinal cancer, head and neck cancer, hepatoma,glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma,non-small cell lung cancer, neural cancer, ovarian cancer, pancreaticcancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, smallcell lung cancer, thyoma, thyroid cancer, testicular cancer andosteosarcoma.

The tyrosine kinase related disorder can be an IGFR-related disorderselected from diabetes, an autoimmune disorder, Alzheimer's and othercognitive disorders, a hyperproliferation disorder, aging, cancer,acromegaly, Crohn's disease, endometriosis, diabetic retinopathy,restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis,an inflammatory disorder and angiogenesis.

Other disorders which might be treated with compounds provided hereininclude, without limitation, immunological and cardiovascular disorderssuch as atherosclerosis.

A disease or condition characterized by ALK activity or expressionincludes but is not limited to ALK-positive anaplastic large celllymphoma, an inflammatory myofibroblastic tumor, diffuse large B-cellnon-Hodgkin lymphoma, non-small cell lung cancer, esophageal carcinoma,breast cancer, neuroblastoma and glioblastoma.

Compositions and Methods of Administration

In certain aspects, provided are compostions comprising a compoundprovided herein. The compositions can be used, for example, in themethods of use described above.

In certain embodiments, a composition provided herein is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms provided herein comprise aprophylactically or therapeutically effective amount of one or moreprophylactic or therapeutic agents (e.g., a compound provided herein, orother prophylactic or therapeutic agent), and one or morepharmaceutically acceptable carriers or excipients or diluents. In aspecific embodiment and in this context, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund'sadjuvant (complete and incomplete)), excipient, or vehicle with whichthe therapeutic is administered. Such pharmaceutical carriers can besterile liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. Water is a particular carrier whenthe pharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Examples of suitable pharmaceutical carriers are described in“Remington's Pharmaceutical Sciences” by E. W. Martin.

On one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well-known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients include starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. Whether a particular excipient is suitablefor incorporation into a pharmaceutical composition or dosage formdepends on a variety of factors well known in the art including, but notlimited to, the way in which the dosage form will be administered to apatient and the specific active ingredients in the dosage form. Thecomposition or single unit dosage form, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.

Lactose-free compositions provided herein can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In one embodiment, lactose-freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

Provided herein are anhydrous pharmaceutical compositions and dosageforms comprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are in certainembodiments anhydrous if substantial contact with moisture and/orhumidity during manufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are in certain embodiments packaged using materials knownto prevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Provided herein are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, tablets, pills, capsules,powders, sustained-release formulations and the like. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such compositions and dosage forms willcontain a prophylactically or therapeutically effective amount of aprophylactic or therapeutic agent in certain embodiments in purifiedform, together with a suitable amount of carrier so as to provide theform for proper administration to the patient. The formulation shouldsuit the mode of administration. In certain embodiments, thepharmaceutical compositions or single unit dosage forms are sterile andin suitable form for administration to a subject, in certain embodimentsan animal subject, such as a mammalian subject, particularly a humansubject.

A pharmaceutical composition provided herein is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, intramuscular, subcutaneous,oral, buccal, sublingual, inhalation, intranasal, transdermal, topical,transmucosal, intra-tumoral, intra-synovial and rectal administration.

In a specific embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous, subcutaneous, intramuscular, oral, intranasal or topicaladministration to human beings.

In an embodiment, a pharmaceutical composition is formulated inaccordance with routine procedures for subcutaneous administration tohuman beings. In one embodiment, compositions for intravenousadministration are solutions in sterile isotonic aqueous buffer. Wherenecessary, the composition may also include a solubilizing agent and alocal anesthetic such as lignocamne to ease pain at the site of theinjection.

Examples of dosage forms include, but are not limited to: tablets;caplets; capsules, such as soft elastic gelatin capsules; cachets;troches; lozenges; dispersions; suppositories; ointments; cataplasms(poultices); pastes; powders; dressings; creams; plasters; solutions;patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosageforms suitable for oral or mucosal administration to a patient,including suspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms provided herein willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disorder may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Also, the therapeutically effective dosage form may vary among differenttypes of cancer. Similarly, a parenteral dosage form may contain smalleramounts of one or more of the active ingredients it comprises than anoral dosage form used to treat the same disease or disorder. These andother ways in which specific dosage forms provided herein will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

The ingredients of compositions provided herein are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

Typical dosage forms comprise a compound provided herein, or apharmaceutically acceptable salt, solvate or hydrate thereof lie withinthe range of from about 0.1 mg to about 1000 mg per day. Particulardosage forms have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0,10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of thecompound.

Oral Dosage Forms

Pharmaceutical compositions provided herein that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

In certain embodiments, the oral dosage forms are solid and preparedunder anhydrous conditions with anhydrous ingredients, as described indetail in the sections above. However, the scope extends beyondanhydrous, solid oral dosage forms. As such, further forms are describedherein.

Typical oral dosage forms provided herein are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms include,but are not limited to, binders, fillers, disintegrants, and lubricants.Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions provided herein istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients should be used to form solid oral dosage formsprovided herein. The amount of disintegrant used varies based upon thetype of formulation, and is readily discernible to those of ordinaryskill in the art. Typical pharmaceutical compositions comprise fromabout 0.5 to about 15 weight percent of disintegrant, specifically fromabout 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulatedaerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.),CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. ofBoston, Mass.), and mixtures thereof. If used at all, lubricants aretypically used in an amount of less than about 1 weight percent of thepharmaceutical compositions or dosage forms into which they areincorporated.

Controlled Release Dosage Forms

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. Examples include, butare not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566,each of which is incorporated herein by reference. Such dosage forms canbe used to provide slow or controlled-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients. Thus provided are singleunit dosage forms suitable for oral administration such as, but notlimited to, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are in certain embodimentssterile or capable of being sterilized prior to administration to apatient. Examples of parenteral dosage forms include, but are notlimited to, solutions ready for injection, dry products ready to bedissolved or suspended in a pharmaceutically acceptable vehicle forinjection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms.

Transdermal, Topical & Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms provided herein include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms provided herein are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients provided herein. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Dosage & Frequency of Administration

The amount of the compound or composition which will be effective in theprevention, treatment, management, or amelioration of a disorder or oneor more symptoms thereof will vary with the nature and severity of thedisease or condition, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each patient depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thepatient. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems.

Exemplary doses of a compound include milligram or microgram amounts ofthe active peptide per kilogram of subject or sample weight (e.g., about1 microgram per kilogram to about 500 milligrams per kilogram, about 100micrograms per kilogram to about 5 milligrams per kilogram, or about 1microgram per kilogram to about 50 micrograms per kilogram). In oneembodiment, the recommended daily dose range of a compound providedherein for the conditions described herein lie within the range of fromabout 0.01 mg to about 1000 mg per day, given as a single once-a-daydose in certain embodiments as divided doses throughout a day. It may benecessary to use dosages of the active ingredient outside the rangesdisclosed herein in some cases, as will be apparent to those of ordinaryskill in the art. Furthermore, it is noted that the clinician ortreating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with individual patient response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compoundsprovided herein are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a patient isadministered multiple dosages of a compound provided herein, not all ofthe dosages need be the same. For example, the dosage administered tothe patient may be increased to improve the prophylactic or therapeuticeffect of the compound or it may be decreased to reduce one or more sideeffects that a particular patient is experiencing.

In certain embodiments, administration of the same compound providedherein may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

Biological Assays

The following assays can be employed in ascertaining the activity of asmall-molecule compound as an inhibitor of the catalytic kinase activityof various tyrosine kinases.

Kinase Assays

To determine inhibition of several tyrosine kinases, such as IGF1R,InsR, Alk, TrkA and Jak2, kinase assays are conducted using eitherKinase-Glo (Promega) or AlphaScreen (PerkinElmer) kinase assayplatforms. The Kinase-Glo Luminescent Kinase Assay is a homogeneousmethod for measuring kinase activity by determining the amount of ATPremaining after a kinase reaction. The luminescent signal isproportional to the amount of ATP and inversely proportional to theamount of kinase activity. Tyrosine kinase PT66 AlphaScreen Assay is ahigh-sensitivity homogeneous, anti-phosphotyrosine antibody-mediatedluminescent proximity method measuring incorporation of phosphate insynthetic poly(Glu-Tyr) substrate. The kinase preparations used consistof purified recombinant, 6×His- or GST-tagged kinase domain fragments ofthe corresponding RTKs expressed in baculovirus system.

Enzymatic Kinase Assay for High-Throughput Screening of Candidate SmallMolecule ALK Inhibitors

High-throughput enzymatic assay may be used to examine ALK activity,modified from the AlphaScreen™ (Amplified Luminescent ProximityHomogeneous Assay) technology marketed by PerkinElmer Life Sciences(Boston, Mass.). This methodology was adapted to assess NPM-ALK activitybased on the ability of the constitutively active purified fusion kinaseto phosphorylate a biotinylated poly(GT) substrate peptide. NPM-ALKactivity is indicated in this assay by a shift in the incident 680 nMwavelength light to an emitted wavelength between 520-620 nM when“donor” and “acceptor” beads come into proximity due to tyrosinephosphorylation by the purified kinase of a biotinylated-poly(GT)(G:T=4:1) peptide bound to the streptavidin-coated “donor” bead andrecognition of this phosphorylation by anti-phosphotyrosine antibodybound to the “acceptor” bead. “Donor” beads contain a photosensitizerthat converts ambient oxygen to the excited singlet state when exposedto laser light at 680 nM. These singlet oxygen molecules diffuse toreact with a thioxene derivative in “acceptor” beads that are inproximity to the “donor” beads (if separated by <200 nM), in turnshifting the emission wavelength to 520-620 nM. In the complete absenceof NPM-ALK activity, the incident and emitted wavelengths are identical(i.e., 680 nM); partial degrees of kinase inhibition can bequantitatively scored based on the amount of wavelength shift.

Compounds with a range of concentrations 40 μM, 20 μM, 10 μM, 5 μM, 2.5μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.15625 μM and 0.078125 μM wereincubated with NPM-ALK, which was produced in insect cells as a6×HIS-tagged fusion protein and purified using nickel-charged resinchromatography, for 30 minutes at RT in the presence of 10 μM ATP and7.0 ng biotinylated poly-GT. A 1:1 mixture of receptor and donor beadswas then added to the reaction and incubated for an additional 60minutes at RT. The assay was conducted on a MultiPROBE liquid handlingworkstation (PerkinElmer) in a 384-well plate format with a totalreaction volume of 40 μL per well. Working stocks of all compounds weredissolved in 100% DMSO and serial dilutions of the compounds wereperformed using kinase buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 5 mMMnCl2, 2 mM DTT (added freshly before use), 0.01% Tween-20) containing5% DMSO. Control samples included on all assays included kinase buffercontaining 5% DMSO without compound, as well as staurosporine, which wehave shown to inhibit NPM-ALK with a Ki of ˜30-50 nM. Data werecollected as optical readings at 520-680 nm on a Fusion™ microplateanalyzer (PerkinElmer), and IC₅₀ and K_(i) values calculated usingPRISM3.0 software (GraphPad Software, Inc., San Diego, Calif.). The sameassay was also used with minor modifications to assess the IC₅₀ andK_(i) values for selected compounds against five other tyrosine kinases(IRK, IGF1R, Flt3, Abl, Src), all of which were purchased fromcommercial vendors. PolyGT-Biotin was bought from CIS BiointernationalCat. #61GT0BLD; ATP—from Sigma Cat. #A7699; sodium orthovanadate—fromSigma Cat. #S-6508; phosphotyrosine (PT66) assay kit from PerkinElmerCat. #6760602M; automated workstation tips (20 μL): PerkinElmer Cat.#6000657; and OptiPlate-384 (white)—from PerkinElmer Cat. #6007299.

Cell-Based XTT Assay for Screening of Small Molecule Inhibitors

The IL-3-dependent lymphoid cell line BaF3 or BaF3 renderedIL-3-independent by engineered expression of NPM-ALK were used inparallel to test each candidate inhibitor. Control wells contained DMSOsolvent without test compound. Specific inhibition of ALK signaling isindicated in the assay by impairment of NPM-ALK-expressing BaF3 cellgrowth without alterations in the growth of parental BaF3. Thiscolorimetric assay of cell proliferation and viability is based uponreduction of the yellow monotetrazolium salt XTT to a water-solubleorange formazan dye, a reaction catalyzed by mitochondrialdehydrogenases in living cells only (Cell Proliferation Kit II, Cat. #1465 015, Roche Biochemicals). In addition to testing compounds for theirability to impair the growth of BaF3 cells engineered to expressNPM-ALK, the NPM-ALK-positive human lymphoma cell line Karpas-299(Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) no.ACC 31), the human BCR-ABL-positive chronic myeloid leukemia cell lineK562 (American Type Culture Collection (ATCC) no. CCL-243), and thehuman T-cell leukemia line Jurkat (DSMZ no. ACC 282) were tested inthese assays.

Each compound stock in 100% DMSO was first diluted using 8% DMSO/culturemedium to produce a working stock of 250 μM compound. This working stockwas then used to perform serial 1:1 dilutions (i.e., 125 μM, 62.5 μM,31.25 μM, 15.625 μM, 7.8125 μM, and 3.90625 μM) using DMSO-free culturemedium. Twenty (20) μL of each of these dilutions was then added to thecells (2×10⁴ cells in 80 μL culture medium per 96-well) to obtain thefinal test compound concentrations (i.e., 25 μM, 12.5 μM, 6.25 μM, 3.125μM, 1.5625 μM, and 0.78125 μM). The maximum final DMSO concentration inthe assays was 2.61%, which was found to have no effect on cellviability and proliferation. The assays were read and the cellular IC₅₀sdetermined 72 hrs. following addition of the test compounds to thecultures.

Compounds according to formula (1) can be prepared according to anymethod apparent to those skilled in the art. Provided below areexemplary methods for their preparation.

wherein

Z¹ is Cl or I; and

AR is selected from optionally substituted aryl or heteroaryl.

This description will be used in the following text.

This scheme was described in J. Med. Chem. 35 (1992), 280-285. Theracemic compounds can be resolved by any of the resolution methods knownin the art, including but not limited to chiral chromatography (e.g.:chromatography on a chiral support column), formation of diastereomericcompounds, either ionic, or covalent, such as chiral tartrate salts orsalts with any feasible chiral acid, carboxylic, or sulfonic. As anexample of covalent compounds the corresponding diastereomeric amides,such as chiral mandelamides, formed by standard non-racemizing amidecoupling reactions, followed by separation either by chromatography, orfractional crystallization.

wherein Y² is selected from hydrogen, bromo or iodo.

The synthesis of the chiral and/or racemic amines is according to theabove general scheme and is a modification of the approach described in:Wagner, Jared M.; McElhinny, Charles J.; Lewin, Anita H.; Carroll, F.Ivy Tetrahedron: Asymmetry (2003), 14(15), 2119-2125.

The non-limiting examples are described below.

EXAMPLES Example 1 General Procedure 1

General Procedure 1. (J. Med. Chem. 35 (1992), 280-285). A mixture ofsubstituted thiophene-2-carbaldehyde (10.0 mmol), nitroethane (10 ml),NH₄OAc (5.0 mmol) was stirred at 110° C. for 4 h. After cooling to RTthe solvent was evaporated, the residue was dissolved in ether (50 ml),washed with water (2×50 ml), the solution was dried over Na₂SO₄,evaporated. The residue was recrystallized from methanol. Precipitatewas collected by filtration, washed with cold (−20° C.) methanol, driedon air.

3-methyl-2-(2-nitroprop-1-en-1-yl)thiophene was prepared according toGeneral Procedure 1. Yellow solid, yield 9%.

¹H NMR (300 MHz, CDCl₃) δ 8.39 (s, 1H), 7.55 (d, J 5.1 Hz, 1H), 7.01 (d,J 5.1 Hz, 1H), 2.57 (s, 3H), 2.43 (s, 3H).

2-methyl-5-(2-nitroprop-1-en-1-yl)thiophene was prepared according toGeneral Procedure 1. Orange solid, yield 49%.

¹H NMR (300 MHz, DMSO) δ 8.32 (s, 1H), 7.60 (d, J 3.6 Hz, 1H), 7.03 (d,J 3.6 Hz, 1H), 2.55 (s, 3H), 2.44 (s, 3H).

3,5-dimethyl-2-(2-nitroprop-1-en-1-yl)thiophene was prepared accordingto General Procedure 1. Orange solid, yield 58%.

¹H NMR (300 MHz, CDCl₃) δ 8.36 (s, 1H), 6.71 (s, 1H), 2.52 (s, 6H), 2.37(s, 3H).

2,3-dimethyl-5-(2-nitroprop-1-en-1-yl)thiophene was prepared accordingto General Procedure 1. Brown solid, yield 98%.

¹H NMR (300 MHz, CDCl₃) δ 8.19 (s, 1H), 7.14 (s, 1H), 2.42 (s, 3H), 2.38(s, 3H), 2.21 (s, 3H).

2-(2-nitroprop-1-en-1-yl)-1-benzothiophene was prepared according toGeneral Procedure 1. Yellow solid, yield 100%.

¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.89 (m, 2H), 8.67 (s, 1H), 7.42(m, 2H), 2.65 (s, 3H).

2-ethyl-5-(2-nitroprop-1-en-1-yl)thiophene was prepared according toGeneral Procedure 1. Brown solid, yield 45%.

¹H NMR (300 MHz, CDCl₃) δ 8.24 (s, 1H), 6.90 (s, 1H), 2.85 (q, J 7.0 Hz2H), 2.54 (s, 3H), 1.37 (t, J 7.0 Hz, 3H).

2-(4-methoxyphenyl)-5-(2-nitroprop-1-en-1-yl)thiophene was preparedaccording to General Procedure 1 using DCM instead of ether. Orangesolid, yield 64%.

¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H), 7.64 (m, 2H), 7.19 (m, 2H), 6.93(m, 2H), 3.84 (s, 3H), 2.60 (s, 3H).

2-(2-nitroprop-1-en-1-yl)-5-phenylthiophene was prepared according toGeneral Procedure 1. Orange solid, yield 73%.

¹H NMR (300 MHz, CDCl₃) δ 8.25 (s, 1H), 7.71 (m, 2H), 7.41 (m, 5H), 2.65(s, 3H).

4-methyl-2-(2-nitroprop-1-en-1-yl)thiophene was prepared according toGeneral Procedure 1. Yellow solid, yield 40%.

¹H NMR (300 MHz, CDCl₃) δ 8.23 (s, 1H), 7.20 (s, 2H), 2.50 (s, 3H), 2.30(s, 3H).

General Procedure 2

General Procedure 2. To a suspension of LAH (0.30 mol) in dry THF (150ml) a solution of 2-(2-nitroprop-1-en-1-yl)thiophene (0.050 mol) in THF(50 ml) was added dropwise over 30 min at 40-50° C. The reaction mixturewas stirred overnight at 60° C. After cooling to RT saturated K₂CO₃ (200ml) was added carefully, extracted with EtOAc (2×200 ml). Extract wasdried over Na₂SO₄, evaporated.

1-(4,5-dimethyl-2-thienyl)propan-2-amine was prepared according toGeneral Procedure 2. Brown oil, yield 52%.

LCMS [M+H]⁺ 170.2.

1-(1-benzothien-2-yl)propan-2-amine was prepared according to GeneralProcedure 2. Brown oil, yield 38%.

LCMS [M+H]⁺ 192.2.

1-(5-ethyl-2-thienyl)propan-2-amine was prepared according to GeneralProcedure 2. Brown oil, yield 47%.

LCMS [M+H]⁺ 170.2.

1-[5-(4-methoxyphenyl)-2-thienyl]propan-2-amine was prepared accordingto General Procedure 2. Brown solid, yield 44%.

LCMS [M+H]⁺ 248.3.

1-(5-phenyl-2-thienyl)propan-2-amine was prepared according to GeneralProcedure 2. Brown oil, yield 58%.

LCMS [M+H]⁺ 218.3.

1-(4-methyl-2-thienyl)propan-2-amine was prepared according to GeneralProcedure 2. Brown oil, yield 46%.

LCMS [M+H]⁺ 156.3.

1-(3,5-dimethyl-2-thienyl)propan-2-amine was prepared according toGeneral Procedure 2. Brown oil, yield 39%.

LCMS [M+H]⁺ 170.3.

General Procedure 3

R—NH₂ depicts a generic promary amine.

General Procedure 3. A mixture of chloropyridone (0.05 mmol), amine(0.05 mmol), EtOH (1.0 ml) and NEt3 (0.1 ml) was stirred at 100° C.overnight. The solvent was evaporated. Acetic acid (2.0 ml) and Zn(dust, 0.1 g) were added, the mixture was stirred at 110° C. for 5 h.Solids were removed by filtration, filtrate was evaporated, and theresidue was separated by preparative TLC (CH₂Cl₂-MeOH—NH₄OH, 100:10:1).

2-(4-{[1-methyl-2-(5-methyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 531.6.

2-(4-{[2-(2-fluorophenyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 529.3.

2-(4-{[1-methyl-2-(3-methyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 531.3.

2-(4-{[1-methyl-2-(4-methyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 531.3

2-(4-{[2-(4,5-dimethyl-2-thienyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 545.3.

2-(4-{[2-(3,5-dimethyl-2-thienyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 545.3.

2-(4-{[(1S)-1-methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 517.4.

2-(4-{[2-(1-benzothien-2-yl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 567.3.

2-(4-{[2-(5-ethyl-2-thienyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 545.5.

2-[4-({2-[5-(4-methoxyphenyl)-2-thienyl]-1-methylethyl}amino)-2-oxo-1,2-dihydropyridin-3-yl]-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 623.5.

2-(4-{[1-methyl-2-(5-phenyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-onewas prepared according to General procedure 3.

LCMS [M+H]⁺ 593.5.

General Procedure 4 ((2R)-1-(aryl)propan-2-ols)

General Procedure 4. Substituted bromobenzene (20 mmol) was dissolved indry THF (100 ml), the solution was cooled to −100° C. (heptane-liquidnitrogen) under Ar. nBuLi (12.5 ml of 1.6 M in hexane, 20 mmol) wasadded dropwise over 10 min at the temperature between −95° C. and −105°C., the mixture was stirred for 10 min at the same temperature. Than(R)-propyleneoxide (1.82 ml, 26 mmol) was added dropwise over 5 min andthe mixture was stirred for 5 min at the temperature between −95° C. and−105° C. BF₃*Et₂O (2.17 ml, 30 mmol) was added dropwise over 5 min, themixture was stirred for 1 h at the temperature between −95° C. and −105°C., saturated NH₄Cl (10 ml) was added at the same temperature and thanthe mixture was stirred overnight wile the temperature was increasing toRT. Water (50 ml) was added, extracted with hexane-EtOAc (1:1, 2×50 ml),extract was dried over Na₂SO₄, evaporated. The residue was separated onSiO₂ (50 ml, hexane-EtOAc 10:1).

(R)-1-(2-fluorophenyl)propan-2-ol

(2R)-1-(2-fluorophenyl)propan-2-ol was prepared according to Generalprocedure 4. ¹H NMR (400 MHz, DMSO-d₆) δ 7.31-7.20 (m, 2H), 7.13-7.08(m, 2H), 4.61 (d, J 4.9 Hz, 1H), 3.89-3.79 (m, 1H), 2.71 (dd, J J 6.4and 13.2 Hz, 1H), 2.60 (dd, J 6.4 and 13.4 Hz, 1H), 1.03 (d, J 6.1 Hz,3H).

(R)-1-(2-chlorophenyl)propan-2-ol

(2R)-1-(2-chlorophenyl)propan-2-ol was prepared according to Generalprocedure 4. ¹H NMR (400 MHz, DMSO-d₆) δ 7.41-7.32 (m, 2H), 7.27-7.19(m, 2H), 4.62 (d, J 5.1 Hz, 1H), 3.94-3.85 (m, 1H), 2.80 (dd, J 6.8 and13.2 Hz, 1H), 2.72 (dd, J 6.2 and 13.2 Hz, 1H), 1.06 (d, J 6.2 Hz, 3H).

General Procedure 5 ((2S)-1-arylpropan-2-amine))

General Procedure 5. To a solution of (2R)-1-arylpropan-2-ol (10 mmol)and NEt3 (2.1 ml, 15 mmol) in DCM (10 ml) MSCl (0.85 ml, 11 mmol) wasadded dropwise over 5 min at 0° C. The reaction mixture was stirred atRT for 4 h. Than the reaction mixture was washed with water (10 ml),organic layer was separated, dried over Na2SO4. The solvent wasevaporated. DMSO (5.0 ml) and NaN₃ were added, the mixture was stirredfor 2 h at 80° C., cooled to RT, hexane (20 ml) was added, the mixturewas washed with water (2×20 ml), and organic layer was dried overNa₂SO₄, evaporated. The residue was dissolved in THF (10 ml), PPh₃ wasadded in portions, at RT and stirring. The reaction mixture was stirredfor 4 h at RT, than NH₄OH (10 ml of 25%) was added, stirred overnight at40° C. After cooling to RT 1N HCl (20 ml) was added, the mixture waswashed with DCM (2×20 ml), the aqueous phase was basified with 1N NaOHto pH 9-10, extracted with DCM (2×20 ml). Extract was dried over Na2SO4,evaporated.

(2S)-1-(2-fluorophenyl)propan-2-amine was prepared according to Generalprocedure 5. Colorless oil, Yield 50%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.29-7.20 (m, 2H), 7.14-7.09 (m, 2H),3.05-2.97 (m, 1H), 2.57-2.50 (m, 2H), 0.94 (d, J 6.1 Hz, 3H).

(2S)-1-(2-chlorophenyl)propan-2-amine was prepared according to Generalprocedure 5. Colorless oil, Yield 55%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41-7.38 (m, 1H), 7.33-7.19 (m, 3H),3.11-3.03 (m, 1H), 2.66 (d, J 6.8 Hz, 2H), 0.96 (d, J 6.4 Hz, 3H).

General Procedure 6

General Procedure 6. A mixture of chloropyridone (0.4 mmol), amine (0.4mmol), NEt3 (0.5 ml) and DMSO (2.0 ml) was stirred overnight at 85° C.The product was isolated by preparative HPLC on C18 column(acetonitrile-01% TFA 5:95 to 95:5 v/v).

2-(4-{[(1S)-2-(2-fluorophenyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionewas prepared according to General procedure 6.

LCMS [M+H]⁺ 529.2

2-(4-{[(1S)-2-(2-chlorophenyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionewas prepared according to General procedure 6.

LCMS [M+H]⁺ 545.2

5-Methoxy-2-methylaniline

5-Methoxy-2-methylaniline: To a solution of4-methoxy-1-methyl-2-nitrobenzene (18.0 g, 108 mmol) in 160 mL of DMEwas added Pd/C (10%, 0.9 g) under nitrogen. Then hydrazine hydrate(16.17 g, 323 mmol) was added dropwise. The mixture was heated andstirred under reflux for 4 h. Then another 3 mL of hydrazine hydrate wasadded and stirred under reflux for 2d. Then the reaction mixture wascooled to RT, filtered through celite and evaporated to dryness to give5-methoxy-2-methylaniline as yellow oil that solidified upon dryingunder vacuum to give 14.8 g (100%). ¹H NMR (300 MHz, CDCl₃): δ 6.94 (d,J=7.53 Hz, 1H), 6.28 (d, J=7.53 Hz, 1H), 6.26 (s, 1H), 3.78 (s, 3H), 3.5(br, 1H), 2.10 (s, 3H), 1.6 (br, 1H).

(2R)-1-(5-Fluoro-2-methoxyphenyl)propan-2-ol

(R)-2-methyloxirane

(2R)-1-(5-Fluoro-2-methoxyphenyl)propan-2-ol: A solution of2-bromo-4-fluoro-1-methoxybenzene (2.0 g, 9.75 mmol) in 20 mL ofanhydrous THF was cooled to −78° C. Then 1.7M solution of t-BuLi inpentane (13.0 mL, 22.1 mmol) was added dropwise. The mixture was stirredat −78° C. for 10 min, then R-(+)-propylene oxide (670 mg, 11.55 mmol)was added and the mixture was allowed to warm to 0° C. overnight. Themixture was quenched with 2 mL of sat. NH₄Cl and then conc. HCl wasadded dropwise to pH 8. The mixture was extracted with EtOAc (2×20 mL),the extract was dried over Na₂SO₄ and evaporated to give crude oil,which was purified by column (silica gel, EtOAc/hexane 1:9) to give(2R)-1-(5-fluoro-2-methoxyphenyl)propan-2-ol (531 mg, 30%). ¹H NMR (300MHz, CDCl₃): δ 6.88 (m, 2H), 6.78 (m, 1H), 4.06 (m, 1H), 3.81 (s, 3H),2.66-2.84 (m, 2H), 1.92 (d, J=3.96 Hz, 1H), 1.22 (d, J=6.21 Hz, 3H).

N-(3-Iodo-4-methylphenyl)-N,N-dimethylamine

N-(3-Iodo-4-methylphenyl)-N,N-dimethylamine: To a solution of3-iodo-4-methylaniline (5.0 g, 21.46 mmol) in 30 mL of THF was addedNaHCO₃ anh. (5.0 g, 60 mmol). The mixture was stirred anddimethylsulfate (5.92 g, 47 mmol) was carefully added. The mixture wasstirred for 16 h, then 12 mL of sat. NaHCO₃ was added and extracted withEtOAc (2×30 mL). The extract was dried over Na₂SO₄ and evaporated togive crude oil, which was purified by column (silica gel, DCM/hexane1:9) to give N-(3-iodo-4-methylphenyl)-N,N-dimethylamine (2.83 g, 51%)as yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.18 (d, J=2.82 Hz, 1H), 7.05(d, J=8.49 Hz, 1H), 7.18 (dd, J₁=8.49 Hz, J₂=2.82 Hz, 1H), 2.88 (s, 6H),2.32 (s, 3H).

1,5-Difluoro-3-iodo-2-(trifluoromethyl)benzene

1,5-Difluoro-3-iodo-2-(trifluoromethyl)benzene: To a solution ofnitrosonium tetrafluoroborate (5.6 g, 48 mmol) in 20 mL of ACN was addedsolution of 3,5-difluoro-2-(trifluoromethyl)aniline (7.88 g, 40 mmol) in10 mL of ACN at −20° C. The mixture was stirred for 1 h raisingtemperature to 0° C. A white precipitate formed. Then a solution of KI(7.97 g, 48 mmol) in 20 mL of water was added dropwise while cooling inan ice bath. The mixture was stirred for 1 h, then added 2 mL ofsaturated sodium sulfite, and the mixture was extracted withEtOAc/hexane 1:1 (2×10 mL). Extract was dried over Na₂SO₄ andconcentrated under light vacuum at 20° C. to give crude reddish oil thatwas distilled under vacuum to give pure1,5-difluoro-3-iodo-2-(trifluoromethyl)benzene as pale oil (9.14 g,62%). ¹H NMR (300 MHz, CDCl₃): δ 7.63 (d, J=7.17 Hz, 1H), 6.94 (t, J=9.6Hz, 1H).

2-Iodo-4-methoxy-1-methylbenzene

2-Iodo-4-methoxy-1-methylbenzene: To a solution of nitrosoniumtetrafluoroborate (5.6 g, 48 mmol) in 30 mL of ACN was added solution of5-methoxy-2-methylaniline (5.49 g, 40 mmol) in 20 mL of ACN at −20° C.The mixture was stirred for 15 min at 0° C. A dark mixture formed. Thena solution of KI (7.97 g, 48 mmol) in 20 mL of water was added dropwisewhile cooling in an ice bath. The mixture was stirred for 1 h, thenadded 2 mL of saturated sodium sulfite, and the mixture was extractedwith EtOAc/hexane 1:1 (2×10 mL). Extract was dried over Na₂SO₄ andevaporated under vacuum at 20° C. to give crude reddish oil that waspassed through silica gel plug with hexane to give pure2-iodo-4-methoxy-1-methylbenzene as colorless oil (3.71 g, 32%). ¹H NMR(300 MHz, CDCl₃): δ 7.35 (s, 1H), 7.11 (d, J=8.46 Hz, 1H), 6.80 (d,J=8.46 Hz, 1H), 3.76 (s, 3H), 2.36 (s, 3H).

(2R)-1-(2-Chloro-5-fluorophenyl)propan-2-ol

(2R)-1-(2-Chloro-5-fluorophenyl)propan-2-ol: A solution of2-bromo-1-chloro-4-fluorobenzene (4.19 g, 20 mmol) in 100 mL ofanhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol)was added dropwise at −100° C. to −90° C. The mixture was stirred at−100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide(1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C.to −90° C., then the mixture was cooled to −105° C. and a 46.5% solutionof BF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. Themixture was stirred at −100° C. to −90° C. for 2 h, then the reactionwas quenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture wasstirred and warmed to 0° C. overnight. Then 20 mL of water was added andmixture was extracted with EtOAc (2×60 mL), the extract was dried overNa₂SO₄ and evaporated to give crude oil, which was purified by column(silica gel, EtOAc/hexane 1:9, Rf=0.52 in EtOAc/hexane 3:7) to give(2R)-1-(2-chloro-5-fluorophenyl)propan-2-ol (2.80 g, 74%) as colorlessoil. ¹H NMR (300 MHz, CDCl₃): δ 7.32 (m, 1H), 7.02 (m, 1H), 6.90 (m,1H), 4.14 (m, 1H), 2.82-2.96 (m, 2H), 1.46 (d, J=4.32 Hz, 1H), 1.28 (d,J=6.21 Hz, 3H).

(2R)-1-(2-Bromo-5-fluorophenyl)propan-2-ol

(2R)-1-(2-Bromo-5-fluorophenyl)propan-2-ol: A solution of1-bromo-4-fluoro-2-iodobenzene (6.02 g, 20 mmol) in 100 mL of anhydrousTHF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was addeddropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to−90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g,1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90°C., then the mixture was cooled to −105° C. and a 46.5% solution of BF₃in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture wasstirred at −100° C. to −90° C. for 2 h, then the reaction was quenchedwith 20 mL of sat. aq. NH₄Cl at −90° C. The mixture was stirred andwarmed to 0° C. overnight. Then 20 mL of water was added and mixture wasextracted with EtOAc (2×60 mL), the extract was dried over Na₂SO₄ andevaporated to give crude oil, which was purified by column (silica gel,EtOAc/hexane 1:9, Rf=0.52 in EtOAc/hexane 3:7) to give(2R)-1-(2-bromo-5-fluorophenyl)propan-2-ol (1.67 g, 35%) as white solid.¹H NMR (300 MHz, CDCl₃): δ 7.50 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H),4.14 (m, 1H), 2.78-2.96 (m, 2H), 1.45 (d, J=4.53 Hz, 1H), 1.29 (d,J=6.24 Hz, 3H).

(2R)-1-[5-(Dimethylamino)-2-methylphenyl]propan-2-ol

(2R)-1-[5-(Dimethylamino)-2-methylphenyl]propan-2-ol: A solution ofN-(3-iodo-4-methylphenyl)-N,N-dimethylamine (5.22 g, 20 mmol) in 100 mLof anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol)was added dropwise at −100° C. to −90° C. The mixture was stirred at−100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide(1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C.to −90° C., then the mixture was cooled to −105° C. and a 46.5% solutionof BF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. Themixture was stirred at −100° C. to −90° C. for 2 h, then the reactionwas quenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture wasstirred and warmed to 0° C. overnight. Then 20 mL of water was added andmixture was extracted with EtOAc (2×60 mL), the extract was dried overNa₂SO₄ and evaporated to give crude oil, which was purified by column(silica gel, EtOAc/hexane 1:9, Rf=0.25 in EtOAc/hexane 3:7) to give(2R)-1-[5-(dimethylamino)-2-methylphenyl]propan-2-ol (0.15 g, 4%) asbrown oil. ¹H NMR (300 MHz, CDCl₃): δ 7.03 (m, 1H), 6.58 (m, 2H), 4.02(m, 1H), 2.90 (s, 6H), 2.65-2.78 (m, 2H), 2.23 (s, 3H), 1.62 (br, 1H),1.29 (d, J=6.21 Hz, 3H).

(2R)-1-[2-Methyl-5-(trifluoromethyl)phenyl]propan-2-ol

(2R)-1-[2-Methyl-5-(trifluoromethyl)phenyl]propan-2-ol: A solution of2-bromo-1-methyl-4-(trifluoromethyl)benzene (4.78 g, 20 mmol) in 100 mLof anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol)was added dropwise at −100° C. to −90° C. The mixture was stirred at−100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide(1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C.to −90° C., then the mixture was cooled to −105° C. and a 46.5% solutionof BF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. Themixture was stirred at −100° C. to −90° C. for 2 h, then the reactionwas quenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture wasstirred and warmed to 0° C. overnight. Then 20 mL of water was added andmixture was extracted with EtOAc (2×60 mL), the extract was dried overNa₂SO₄ and evaporated to give crude oil, which was purified by column(silica gel, EtOAc/hexane 1:9, Rf=0.45 in EtOAc/hexane 3:7) to give(2R)-1-[2-methyl-5-(trifluoromethyl)phenyl]propan-2-ol (2.87 g, 66%) aswhite solid. ¹H NMR (300 MHz, CDCl₃): δ 7.42 (s, 1H), 7.39 (d, J=8.1 Hz,1H), 7.27 (d, J=8.1 Hz, 1H), 4.06 (m, 1H), 2.81 (d, J=6.39 Hz, 2H), 2.39(s, 3H), 1.43 (d, J=4.14 Hz, 1H), 1.29 (d, J=6.21 Hz, 3H).

(2R)-1-(2,3,5-Trifluorophenyl)propan-2-ol

(2R)-1-(2,3,5-Trifluorophenyl)propan-2-ol: A solution of1-bromo-2,3,5-trifluorobenzene (4.22 g, 20 mmol) in 100 mL of anhydrousTHF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was addeddropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to−90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g,1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90°C., then the mixture was cooled to −105° C. and a 46.5% solution of BF₃in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture wasstirred at −100° C. to −90° C. for 2 h, then the reaction was quenchedwith 20 mL of sat. aq. NH₄Cl at −90° C. The mixture was stirred andwarmed to 0° C. overnight. Then 20 mL of water was added and mixture wasextracted with EtOAc (2×60 mL), the extract was dried over Na₂SO₄ andevaporated to give crude oil, which was purified by column (silica gel,EtOAc/hexane 1:9, Rf=0.52 in EtOAc/hexane 3:7) to give(2R)-1-(2,3,5-trifluorophenyl)propan-2-ol (3.14 g, 83%) as pale yellowoil. ¹H NMR (300 MHz, CDCl₃): δ 7.12-7.26 (m, 1H), 6.76-6.96 (m, 1H),4.09 (m, 1H), 2.85-2.88 (m, 2H), 1.47 (d, J=5.46 Hz, 1H), 1.26 (d,J=6.03 Hz, 3H).

(1S)-2-(2-Chloro-5-fluorophenyl)-1-methylethyl azide

(1S)-2-(2-Chloro-5-fluorophenyl)-1-methylethyl azide: A solution of(2R)-1-(2-chloro-5-fluorophenyl)propan-2-ol (1.40 g, 7.42 mmol) and DIEA(2.58 mL, 14 mmol) in 20 mL of anhydrous DCM was cooled to −10° C. ThenMSCl (1.02 g, 8.9 mmol) was carefully added and the mixture was warmedto RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was added andthe mixture was extracted with DCM (2×20 mL). The extract was dried overNa₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 6 mL of anh. DMF. Then NaN₃ (965 mg, 14.84 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil, which was passedthrough silica gel plug eluting with 5% DCM in hexane, then evaporatedto give (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethyl azide (1.22 g,77%) as pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.32 (m, 1H), 6.98(m, 2H), 3.80 (m, 1H), 2.88 (d, J=5.1 Hz, 2H), 1.31 (d, J=6.39 Hz, 3H).

(1S)-2-(2-Bromo-5-fluorophenyl)-1-methylethyl azide

(1S)-2-(2-Bromo-5-fluorophenyl)-1-methylethyl azide: A solution of(2R)-1-(2-bromo-5-fluorophenyl)propan-2-ol (1.06 g, 4.55 mmol) and DIEA(1.58 mL, 9.1 mmol) in 20 mL of anhydrous DCM was cooled to −10° C. ThenMSCl (625 mg, 5.46 mmol) was carefully added and the mixture was warmedto RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was added andthe mixture was extracted with DCM (2×20 mL). The extract was dried overNa₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 4 mL of anh. DMF. Then NaN₃ (592 mg, 9.1 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil, which was passedthrough silica gel plug eluting with 5% DCM in hexane, then evaporatedto give (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethyl azide (997 mg,85%) as pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.51 (m, 1H), 6.99(m, 1H), 6.86 (m, 1H), 3.81 (m, 1H), 2.88 (d, J=4.9 Hz, 2H), 1.32 (d,J=4.35 Hz, 3H).

N-{3-[(2S)-2-Azidopropyl]-4-methylphenyl}-N,N-dimethylamine

N-{3-[(2S)-2-Azidopropyl]-4-methylphenyl}-N,N-dimethylamine: A solutionof (2R)-1-[5-(dimethylamino)-2-methylphenyl]propan-2-ol (150 mg, 0.77mmol) and DIEA (0.27 mL, 1.54 mmol) in 10 mL of anhydrous DCM was cooledto −10° C. Then MsCl (107 mg, 0.93 mmol) was carefully added and themixture was warmed to RT and stirred for 30 min. Then 5 mL of sat.NaHCO₃ was added and the mixture was extracted with DCM (2×10 mL). Theextract was dried over Na₂SO₄ and evaporated to give crude oil ofmesylate. This oil was dissolved in 2 mL of anh. DMF. Then NaN₃ (100 mg,1.54 mmol) was added and the mixture was heated at 80° C. for 2 h. Then20 mL of water added and extracted with 2×10 mL of EtOAc/hexane 1:1mixture. The extract was dried over Na₂SO₄ and evaporated to give crudeoil, which was passed through silica gel plug eluting with 5% DCM inhexane, then evaporated to giveN-{3-[(2S)-2-azidopropyl]-4-methylphenyl}-N,N-dimethylamine (71 mg, 42%)as pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.02 (m, 1H), 6.57 (m,2H), 3.66 (m, 1H), 2.90 (s, 6H), 2.64-2.84 (m, 2H), 2.23 (s, 3H), 1.28(d, J=6.42 Hz, 3H).

(1S)-1-Methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethyl azide

(1S)-1-Methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethyl azide: Asolution of (2R)-1-[2-methyl-5-(trifluoromethyl)phenyl]propan-2-ol (1.62g, 7.42 mmol) and DIEA (2.58 mL, 14 mmol) in 20 mL of anhydrous DCM wascooled to −10° C. Then MsCl (1.02 g, 8.9 mmol) was carefully added andthe mixture was warmed to RT and stirred for 30 min. Then 10 mL of sat.NaHCO₃ was added and the mixture was extracted with DCM (2×20 mL). Theextract was dried over Na₂SO₄ and evaporated to give crude oil ofmesylate. This oil was dissolved in 6 mL of anh. DMF. Then NaN₃ (965 mg,14.84 mmol) was added and the mixture was heated at 80° C. for 2 h. Then30 mL of water added and extracted with 20 mL of EtOAc/hexane 1:1mixture. The extract was dried over Na₂SO₄ and evaporated to give crudeoil, which was passed through silica gel plug eluting with 5% DCM inhexane, then evaporated to give(1S)-1-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethyl azide (1.64 g,91%) as pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.40 (m, 2H), 7.27(m, 1H), 3.70 (m, 1H), 2.73-2.92 (m, 2H), 2.39 (s, 3H), 1.31 (d, J=6.39Hz, 31-1).

(1S)-1-Methyl-2-(2,3,5-trifluorophenyl)ethyl azide

(1S)-1-Methyl-2-(2,3,5-trifluorophenyl)ethyl azide: A solution of(2R)-1-(2,3,5-trifluorophenyl)propan-2-ol (1.41 g, 7.42 mmol) and DIEA(2.58 mL, 14 mmol) in 20 mL of anhydrous DCM was cooled to −10° C. ThenMsCl (1.02 g, 8.9 mmol) was carefully added and the mixture was warmedto RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was added andthe mixture was extracted with DCM (2×20 mL). The extract was dried overNa₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 6 mL of anh. DMF. Then NaN₃ (965 mg, 14.84 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil, which was passedthrough silica gel plug eluting with 5% DCM in hexane, then evaporatedto give (1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethyl azide (931 mg, 58%)as pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.03 (m, 1H), 6.81 (m,1H), 3.73 (m, 1H), 2.84 (m, 2H), 1.32 (d, J=6.6 Hz, 3H).

(1S)-2-(2-Chloro-5-fluorophenyl)-1-methylethylamine

(1S)-2-(2-Chloro-5-fluorophenyl)-1-methylethylamine: To a solution of(1S)-2-(2-chloro-5-fluorophenyl)-1-methylethyl azide (1.10 g, 5.15 mmol)in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture washydrogenated under hydrogen balloon for 30 min. The catalyst was removedby filtration through celite, then passed through silica gel plugeluting first with EtOAc (40 mL), then MeOH/EtOAc/NH₄OH 20:75:5 (120mL). The fraction with product was evaporated to give(1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine (721 mg, 67%) aspale yellow oil. ESI-MS: m/z (MH⁺) 188.3. ¹H NMR (300 MHz, CDCl₃): δ7.30 (m, 1H), 6.86-6.97 (m, 2H), 3.26 (m, 1H), 2.66-2.84 (m, 2H), 1.40(s, 2H), 1.15 (d, J=6.42 Hz, 3H).

(1S)-2-(2-Bromo-5-fluorophenyl)-1-methylethylamine

(1S)-2-(2-Bromo-5-fluorophenyl)-1-methylethylamine: To a solution of(1S)-2-(2-bromo-5-fluorophenyl)-1-methylethyl azide (1.00 g, 3.87 mmol)in 20 mL of THF and 4 mL of water was added PPh₃ (2.03 g, 7.74 mmol) andthe mixture was stirred for 4 h. The solvent was evaporated and theresidue was purified by silica gel column eluting first with DCM, thenDCM:MeOH:NH₄OH (94:5:1). The fraction with product was evaporated togive (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamine (134 mg, 15%) ascolorless oil. ¹H NMR (300 MHz, CDCl₃): δ 7.50 (m, 1H), 6.97 (m, 1H),6.83 (m, 1H), 3.28 (m, 1H), 2.66-2.87 (m, 2H), 1.68 (s, 2H), 1.17 (d,J=6.21 Hz, 3H).

N-{3-[(2S)-2-Aminopropyl]-4-methylphenyl}-N,N-dimethylamine

N-{3-[(2S)-2-Aminopropyl]-4-methylphenyl}-N,N-dimethylamine: To asolution of N-{3-[(2S)-2-azidopropyl]-4-methylphenyl}-N,N-dimethylamine(71 mg, 0.325 mmol) in 10 mL of EtOAc was added Pd/C (30 mg of 10% Pd)and the mixture was hydrogenated under hydrogen balloon for 1 h. Thecatalyst was removed by filtration through celite, then passed throughsilica gel plug eluting first with EtOAc (10 mL), then MeOH/EtOAc/NH₄OH20:75:5 (20 mL). The fraction with product was evaporated to giveN-{3-[(2S)-2-aminopropyl]-4-methylphenyl}-N,N-dimethylamine (53 mg, 85%)as pale yellow oil. ESI-MS: m/z (MH⁺) 193.1. ¹H NMR (300 MHz, CDCl₃): δ7.02 (m, 1H), 6.57 (m, 2H), 3.16 (m, 1H), 2.90 (s, 6H), 2.44-2.74 (m,2H), 2.22 (s, 3H), 1.48 (s, 2H), 1.14 (d, J=6.42 Hz, 3H).

(1S)-1-Methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethylamine

(1S)-1-Methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethylamine: To asolution of (1S)-1-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethylazide (1.64 g, 6.74 mmol) in 100 mL of EtOAc was added Pd/C (300 mg of10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h.The catalyst was removed by filtration through celite, then passedthrough silica gel plug eluting first with EtOAc (40 mL), thenMeOH/EtOAc/NH₄OH 20:75:5 (120 mL). The fraction with product wasevaporated to give(1S)-1-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethylamine (1.10 g,75%) as pale yellow oil. ESI-MS: m/z (MH⁺) 218.4. ¹H NMR (300 MHz,CDCl₃): δ 7.37 (m, 2H), 7.20 (m, 1H), 3.20 (m, 1H), 2.58-2.77 (m, 2H),2.38 (s, 3H), 1.42 (s, 2H), 1.14 (d, J=6.21 Hz, 3H).

(1S)-1-Methyl-2-(2,3,5-trifluorophenyl)ethylamine

(1S)-1-Methyl-2-(2,3,5-trifluorophenyl)ethylamine: To a solution of(1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethyl azide (930 mg, 4.32 mmol)in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture washydrogenated under hydrogen balloon for 1 h. The catalyst was removed byfiltration through celite, then passed through silica gel plug elutingfirst with EtOAc (40 mL), then MeOH/EtOAc/NH₄OH 20:75:5 (120 mL). Thefraction with product was evaporated to give(1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethylamine (475 mg, 58%) as paleyellow oil. ESI-MS: m/z (MH⁺) 190.1. ¹H NMR (300 MHz, CDCl₃): δ 7.04 (m,1H), 6.83 (m, 1H), 4.06 (s, 2H), 3.42 (m, 1H), 2.92 (m, 2H), 1.29 (d,J=6.21 Hz, 3H).

2-(4-((1S)-2-(2-Chloro-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one

2-(4-((1S)-2-(2-Chloro-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one:A solution of2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(50 mg, 0.126 mmol), (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine(30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH washeated at 80° C. for 24 h. Then the solvent was evaporated and theresidue was purified by column (silica gel, DCM:MeOH 9:1) to give2-(4-((1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(25 mg, 36%) as pale yellow oil. ESI-MS: m/z (MH⁺) 549.5. ¹H NMR (300MHz, CD₃OD): δ 8.0 (d, J=60.6 Hz, 1H), 7.67 (d, J=52.5 Hz, 1H), 7.33 (m,1H), 7.15 (m, 2H), 6.89 (m, 1H), 6.09 (m, 1H), 4.66 (m, 2H), 3.98 (m,2H), 3.68 (m, 1H), 3.30 (m, 2H), 3.15 (m, 6H), 2.02 (m, 4H), 1.43 (d,J=6.60 Hz, 3H).

2-(4-((1S)-2-(2-Bromo-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one

2-(4-((1S)-2-(2-Bromo-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one:A solution of2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(50 mg, 0.126 mmol), (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamine(48 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH washeated at 80° C. for 24 h. Then the solvent was evaporated and theresidue was purified by column (silica gel, DCM:MeOH 9:1) to give2-(4-((1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(17 mg, 23%) as yellow solid. ESI-MS: m/z (MH⁺) 593.0. ¹H NMR (300 MHz,CDCl₃): δ 8.04 (d, J=58.6 Hz, 1H), 7.53 (d, J=80.9 Hz, 1H), 7.47 (m,1H), 7.15 (m, 2H), 6.80 (m, 1H), 6.00 (m, 1H), 4.56 (m, 2H), 4.13 (m,1H), 3.82 (m, 2H), 3.10 (m, 2H), 2.83 (m, 2H), 2.65 (m, 4H), 1.80 (m,4H), 1.43 (d, J=6.60 Hz, 3H).

2-(4-((1S)-2-(5-Cloro-2-methylphenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one

2-(4-((1S)-2-(5-Cloro-2-methylphenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one:A solution of2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(50 mg, 0.126 mmol), (1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine(30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH washeated at 80° C. for 24 h. Then the solvent was evaporated and theresidue was purified by column (silica gel, DCM:MeOH 95:5) to give2-(4-((1S)-2-(5-cloro-2-methylphenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(41 mg, 59%) as yellow solid. ESI-MS: m/z (MH⁺) 545.5. ¹H NMR (300 MHz,CDCl₃): δ 7.96 (d, J=44.8 Hz, 1H), 7.51 (d, J=66.3 Hz, 1H), 7.20 (m,2H), 7.03 (m, 2H), 5.86 (m, 1H), 4.59 (m, 2H), 3.93 (m, 3H), 2.96-3.13(m, 8H), 2.32 (s, 3H), 1.91 (m, 4H), 1.38 (d, J=7.35 Hz, 3H).

(2R)-1-(5-Chloro-2-methylphenyl)propan-2-ol

(2R)-1-(5-Chloro-2-methylphenyl)propan-2-ol: A solution of4-chloro-2-iodo-1-methylbenzene (5.05 g, 20 mmol) in 100 mL of anhydrousTHF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was addeddropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to−90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g,1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90°C., then the mixture was cooled to −105° C. and a 46.5% solution of BF₃in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture wasstirred at −100° C. to −90° C. for 2 h, then the reaction was quenchedwith 20 mL of sat. aq. NH₄Cl at −90° C. The mixture was stirred andwarmed to 0° C. overnight. Then 20 mL of water was added and mixture wasextracted with EtOAc (2×60 mL), the extract was dried over Na₂SO₄ andevaporated to give crude oil, which was purified by column (silica gel,EtOAc/hexane 1:9, Rf=0.43 in EtOAc/hexane 3:7) to give(2R)-1-(5-chloro-2-methylphenyl)propan-2-ol (1.39 g, 38%) as pale yellowoil. ¹H NMR (300 MHz, CDCl₃): δ 7.16 (s, 1H), 7.10 (m, 2H), 4.03 (m,1H), 2.73 (m, 2H), 2.29 (s, 3H), 1.86 (s, 1H), 1.27 (d, J=6.24 Hz, 3H).

(2R)-1-(3,4-Difluoro-2-methylphenyl)propan-2-ol

(2R)-1-(3,4-Difluoro-2-methylphenyl)propan-2-ol: A solution of1-bromo-3,4-difluoro-2-methylbenzene (4.14 g, 20 mmol) in 100 mL ofanhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol)was added dropwise at −100° C. to −90° C. The mixture was stirred at−100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide(1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C.to −90° C., then the mixture was cooled to −105° C. and a 46.5% solutionof BF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. Themixture was stirred at −100° C. to −90° C. for 2 h, then the reactionwas quenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture wasstirred and warmed to 0° C. overnight. Then 20 mL of water was added andmixture was extracted with EtOAc (2×60 mL), the extract was dried overNa₂SO₄ and evaporated to give crude oil, which was purified by column(silica gel, EtOAc/hexane 1:9, Rf=0.37 in EtOAc/hexane 3:7) to give(2R)-1-(3,4-difluoro-2-methylphenyl)propan-2-ol (2.64 g, 71%) as paleoil. ¹H NMR (300 MHz, CDCl₃): δ 6.85-7.26 (m, 2H), 3.98 (m, 1H), 2.73(m, 2H), 2.25 (m, 3H), 1.45 (d, J=3.75 Hz, 1H), 1.26 (d, J=6.21 Hz, 3H).

(2R)-1-(3,5-Difluoro-2-methylphenyl)propan-2-ol

(2R)-1-(3,5-Difluoro-2-methylphenyl)propan-2-ol: A solution of1,5-difluoro-3-iodo-2-methylbenzene (5.08 g, 20 mmol) in 100 mL ofanhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol)was added dropwise at −100° C. to −90° C. The mixture was stirred at−100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide(1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C.to −90° C., then the mixture was cooled to −105° C. and a 46.5% solutionof BF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. Themixture was stirred at −100° C. to −90° C. for 2 h, then the reactionwas quenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture wasstirred and warmed to 0° C. overnight. Then 20 mL of water was added andmixture was extracted with EtOAc (2×60 mL), the extract was dried overNa₂SO₄ and evaporated to give crude oil, which was purified by column(silica gel, EtOAc/hexane 1:9, Rf=0.45 in EtOAc/hexane 3:7) to give(2R)-1-(3,5-difluoro-2-methylphenyl)propan-2-ol (1.20 g, 32%) as paleyellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.02 (t, J=8.47 Hz, 1H), 6.75 (t,J=9.6 Hz, 1H), 4.04 (m, 1H), 2.69-2.76 (m, 2H), 2.22 (s, 3H), 1.46 (d,J=4.35 Hz, 1H), 1.24 (d, J=6.21 Hz, 3H).

(2R)-1-(2,3,5,6-Tetrafluorophenyl)propan-2-ol

(2R)-1-(2,3,5,6-Tetrafluorophenyl)propan-2-ol: A solution of1-bromo-2,3,5,6-tetrafluorobenzene (4.58 g, 20 mmol) in 100 mL ofanhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol)was added dropwise at −100° C. to −90° C. The mixture was stirred at−100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide(1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C.to −90° C., then the mixture was cooled to −105° C. and a 46.5% solutionof BF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. Themixture was stirred at −100° C. to −90° C. for 2 h, then the reactionwas quenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture wasstirred and warmed to 0° C. overnight. Then 20 mL of water was added andmixture was extracted with EtOAc (2×60 mL), the extract was dried overNa₂SO₄ and evaporated to give crude oil, which was purified by column(silica gel, EtOAc/hexane 1:9, Rf=0.57 in EtOAc/hexane 3:7) to give(2R)-1-(2,3,5,6-tetrafluorophenyl)propan-2-ol (2.57 g, 62%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃): δ 6.96 (m, 1H), 4.11 (m, 1H), 2.89 (m,2H), 1.47 (d, J=5.46 Hz, 1H), 1.29 (d, J=6.21 Hz, 3H).

(1S)-2-(5-Chloro-2-methylphenyl)-1-methylethyl azide

(1S)-2-(5-Chloro-2-methylphenyl)-1-methylethyl azide: A solution of(2R)-1-(5-chloro-2-methylphenyl)propan-2-ol (840 mg, 4.55 mmol) and DIEA(1.58 mL, 9.1 mmol) in 20 mL of anhydrous DCM was cooled to −10° C. ThenMsCl (625 mg, 5.46 mmol) was carefully added and the mixture was warmedto RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was added andthe mixture was extracted with DCM (2×20 mL). The extract was dried overNa₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 4 mL of anh. DMF. Then NaN₃ (592 mg, 9.1 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil, which was passedthrough silica gel plug eluting with 5% DCM in hexane, then evaporatedto give (1S)-2-(5-chloro-2-methylphenyl)-1-methylethyl azide (745 mg,78%) as pale oil. ¹H NMR (300 MHz, CDCl₃): δ 7.13 (m, 3H), 3.67 (m, 1H),2.64-2.85 (m, 2H), 2.29 (s, 3H), 1.29 (d, J=6.6 Hz, 3H).

(1S)-2-(5-Chloro-2-methylphenyl)-1-methylethylamine

(1S)-2-(5-Chloro-2-methylphenyl)-1-methylethylamine: To a solution of(1S)-2-(5-chloro-2-methylphenyl)-1-methylethyl azide (500 mg, 2.38 mmol)in 50 mL of EtOAc was added Pd/C (150 mg of 10% Pd) and the mixture washydrogenated under hydrogen balloon for 20 min. The catalyst was removedby filtration through celite, then passed through silica gel plugeluting first with EtOAc (40 mL), then MeOH/EtOAc/NH₄OH 20:75:5 (120mL). The fraction with product was evaporated to give(1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine (210 mg, 48%) aspale oil. ESI-MS: m/z (MH⁺) 184.4. ¹H NMR (300 MHz, CDCl₃): δ 7.12 (s,1H), 7.08 (s, 2H), 3.16 (m, 1H), 2.48-2.70 (m, 2H), 2.28 (s, 3H), 1.23(s, 2H), 1.13 (d, J=6.21 Hz, 3H).

(1S)-2-(3,4-Difluoro-2-methylphenyl)-1-methylethyl azide

(1S)-2-(3,4-Difluoro-2-methylphenyl)-1-methylethyl azide: A solution of(2R)-1-(3,4-difluoro-2-methylphenyl)propan-2-ol (847 mg, 4.55 mmol) andDIEA (1.58 mL, 9.1 mmol) in 20 mL of anhydrous DCM was cooled to −10° C.Then MsCl (625 mg, 5.46 mmol) was carefully added and the mixture waswarmed to RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was addedand the mixture was extracted with DCM (2×20 mL). The extract was driedover Na₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 4 mL of anh. DMF. Then NaN₃ (592 mg, 9.1 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil, which was passedthrough silica gel plug eluting with 5% DCM in hexane, then evaporatedto give (1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethyl azide (771mg, 80%) as pale oil. ¹H NMR (300 MHz, CDCl₃): δ 6.86 (m, 2H), 3.62 (m,1H), 2.79 (m, 2H), 2.26 (s, 3H), 1.28 (d, J=6.6 Hz, 3H).

(1S)-2-(3,4-Difluoro-2-methylphenyl)-1-methylethylamine

(1S)-2-(3,4-Difluoro-2-methylphenyl)-1-methylethylamine: To a solutionof (1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethyl azide (503 mg,2.38 mmol) in 50 mL of EtOAc was added Pd/C (150 mg of 10% Pd) and themixture was hydrogenated under hydrogen balloon for 1 h. The catalystwas removed by filtration through celite, then passed through silica gelplug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH₄OH 20:75:5(120 mL). The fraction with product was evaporated to give(1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethylamine (376 mg, 85%) aspale oil. ESI-MS: m/z (MH⁺) 186.4. ¹H NMR (300 MHz, CDCl₃): δ 6.82-6.97(m, 2H), 3.12 (m, 1H), 2.48-2.73 (m, 2H), 2.25 (s, 3H), 1.34 (s, 2H),1.12 (d, J=6.39 Hz, 3H).

(2R)-1-(2,5-Dimethoxyphenyl)propan-2-ol

(2R)-1-(2,5-Dimethoxyphenyl)propan-2-ol: A solution of2-bromo-1,4-dimethoxybenzene (4.35 g, 20 mmol) in 100 mL of anhydrousTHF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was addeddropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to−90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g,1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90°C., then the mixture was cooled to −105° C. and a 46.5% solution of BF₃in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture wasstirred at −100° C. to −90° C. for 2 h, then the reaction was quenchedwith 20 mL of sat. aq. NH₄Cl at −90° C. The mixture was stirred andwarmed to 0° C. overnight. Then 20 mL of water was added and mixture wasextracted with EtOAc (2×60 mL), the extract was dried over Na₂SO₄ andevaporated to give crude oil, which was purified by column (silica gel,EtOAc/hexane 1:9, Rf=0.45 in EtOAc/hexane 3:7) to give(2R)-1-(2,5-dimethoxyphenyl)propan-2-ol (2.78 g, 71%) as colorless oil.¹H NMR (300 MHz, CDCl₃): δ 6.79 (m, 1H), 6.74 (m, 2H), 4.05 (m, 1H),3.79 (s, 3H), 3.77 (s, 3H), 2.65-2.86 (m, 2H), 2.10 (d, J=3.39 Hz, 1H),1.22 (d, J=6.21 Hz, 3H).

(2R)-1-(5-Methoxy-2-methylphenyl)propan-2-ol

(2R)-1-(5-Methoxy-2-methylphenyl)propan-2-ol: A solution of2-iodo-4-methoxy-1-methylbenzene (3.70 g, 14.9 mmol) in 100 mL ofanhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) undernitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (11.3 mL, 15.8mmol) was added dropwise at −100° C. to −90° C. The mixture was stirredat −100° C. to −90° C. for 10 min, then a solution of R-(+)-propyleneoxide (1.35 mL, 19.4 mmol) in 15 mL of THF was added dropwise at −100°C. to −90° C., then the mixture was cooled to −105° C. and a 46.5%solution of BF₃ in diethyl ether (3.14 mL, 22.5 mmol) was addeddropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, thenthe reaction was quenched with 20 mL of sat. aq. NH₄Cl at −90° C. Themixture was stirred and warmed to 0° C. overnight. Then 20 mL of waterwas added and mixture was extracted with EtOAc (2×60 mL), the extractwas dried over Na₂SO₄ and evaporated to give crude oil, which waspurified by column (silica gel, EtOAc/hexane 1:9, Rf=0.50 inEtOAc/hexane 3:7) to give (2R)-1-(5-methoxy-2-methylphenyl)propan-2-ol(0.49 g, 18%) as pale oil. ¹H NMR (300 MHz, CDCl₃): δ 7.08 (d, J=8.31Hz, 1H), 6.73 (m, 2H), 4.02 (m, 1H), 3.78 (s, 3H), 2.64-2.80 (m, 2H),2.26 (s, 3H), 1.54 (d, J=3.39 Hz, 1H), 1.27 (d, J=6.03 Hz, 3H).

(2R)-1-(2,3-Difluoro-5,6-dimethoxyphenyl)propan-2-ol

(2R)-1-(2,3-Difluoro-5,6-dimethoxyphenyl)propan-2-ol: A solution of1,2-difluoro-4,5-dimethoxybenzene (3.48 g, 20 mmol) in 10 mL ofanhydrous THF was slowly added to a cooled at −78° C. solution ofsec-BuLi in THF/cyclohexane (1.4M in cyclohexane, 15 mL, 21 mmol mixedwith 80 mL of THF). The mixture was stirred at −70° C. for 10 min, thena solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mLof THF was added dropwise at −100° C. to −90° C., then the mixture wascooled to −105° C. and a 46.5% solution of BF₃ in diethyl ether (4.18mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to−90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq.NH₄Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight.Then 20 mL of water was added and mixture was extracted with EtOAc (2×60mL), the extract was dried over Na₂SO₄ and evaporated to give crude oil,which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.29 inEtOAc/hexane 3:7) to give(2R)-1-(2,3-difluoro-5,6-dimethoxyphenyl)propan-2-ol (883 mg, 19%) aspale oil. ¹H NMR (300 MHz, CDCl₃): δ 6.65 (m, 1H), 4.06 (m, 1H), 3.83(s, 3H), 3.82 (s, 3H), 2.87 (m, 2H), 2.05 (d, J=4.71 Hz, 1H), 1.25 (d,J=6.24 Hz, 3H).

(2R)-1-(2-Ethylphenyl)propan-2-ol

(2R)-1-(2-Ethylphenyl)propan-2-ol: A solution of 1-bromo-2-ethylbenzene(3.70 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −78° C.(liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi incyclohexane (15 mL, 21 mmol) was added dropwise at −78° C. The mixturewas stirred for 10 min, then a solution of R-(+)-propylene oxide (1.51g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to−90° C., then the mixture was cooled to −105° C. and a 46.5% solution ofBF₃ in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixturewas stirred at −100° C. to −90° C. for 2 h, then the reaction wasquenched with 20 mL of sat. aq. NH₄Cl at −90° C. The mixture was stirredand warmed to 0° C. overnight. Then 20 mL of water was added and mixturewas extracted with EtOAc (2×60 mL), the extract was dried over Na₂SO₄and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.55 in EtOAc/hexane 3:7) to give(2R)-1-(2-ethylphenyl)propan-2-ol (877 mg, 26%) as pale yellow oil. ¹HNMR (300 MHz, CDCl₃): δ 7.19 (m, 4H), 4.02 (m, 1H), 2.80 (m, 2H), 2.68(q, J=7.53 Hz, 2H), 1.51 (s, 1H), 1.28 (d, J=6.21 Hz, 3H), 1.22 (t,J=7.53 Hz, 3H).

(S)-2-(5-Methoxy-2-methyl-phenyl)-1-methyl-ethylamine

(S)-2-(5-Methoxy-2-methyl-phenyl)-1-methyl-ethylamine: A solution of(R)-1-(5-methoxy-2-methyl-phenyl)-propan-2-ol (487 mg, 2.7 mmol) andDIEA (0.94 mL, 5.4 mmol) in 20 mL of anhydrous DCM was cooled to −10° C.Then MsCl (371 mg, 3.24 mmol) was carefully added and the mixture waswarmed to RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was addedand the mixture was extracted with DCM (2×20 mL). The extract was driedover Na₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 3 mL of anh. DMF. Then NaN₃ (351 mg, 5.4 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil of azide, which wasdissolved in 50 mL of EtOAc, then Pd/C (150 mg of 10% Pd) was added andthe mixture was hydrogenated under hydrogen balloon for 1 h. Thecatalyst was removed by filtration through celite, the mixture wasevaporated and the crude residue was used directly in the next step.

(S)-2-(2,3-Difluoro-5,6-dimethoxy-phenyl)-1-methyl-ethylamine

(S)-2-(2,3-Difluoro-5,6-dimethoxy-phenyl)-1-methyl-ethylamine: Asolution of (R)-1-(2,3-difluoro-5,6-dimethoxy-phenyl)-propan-2-ol (672mg, 2.7 mmol) and DIEA (0.94 mL, 5.4 mmol) in 20 mL of anhydrous DCM wascooled to −10° C. Then MsCl (371 mg, 3.24 mmol) was carefully added andthe mixture was warmed to RT and stirred for 30 min. Then 10 mL of sat.NaHCO₃ was added and the mixture was extracted with DCM (2×20 mL). Theextract was dried over Na₂SO₄ and evaporated to give crude oil ofmesylate. This oil was dissolved in 3 mL of anh. DMF. Then NaN₃ (351 mg,5.4 mmol) was added and the mixture was heated at 80° C. for 2 h. Then30 mL of water added and extracted with 20 mL of EtOAc/hexane 1:1mixture. The extract was dried over Na₂SO₄ and evaporated to give crudeoil of azide, which was dissolved in 50 mL of EtOAc, then Pd/C (150 mgof 10% Pd) was added and the mixture was hydrogenated under hydrogenballoon for 1 h. The catalyst was removed by filtration through celite,then purified by column (MeOH/EtOAc/NH₄OH 5:93:2) to give(S)-2-(2,3-difluoro-5,6-dimethoxy-phenyl)-1-methyl-ethylamine (300 mg,48%) as pale oil. ESI-MS: m/z (MH⁺) 232.2. ¹H NMR (300 MHz, CDCl₃): δ6.63 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.17 (m, 1H), 2.63-2.78 (m,2H), 1.32 (br., 2H), 1.13 (d, J=6.21 Hz, 3H).

(S)-2-(2-Ethyl-phenyl)-1-methyl-ethylamine

(S)-2-(2-Ethyl-phenyl)-1-methyl-ethylamine: A solution of(R)-1-(2-ethyl-phenyl)-propan-2-ol (443 mg, 2.7 mmol) and DIEA (0.94 mL,5.4 mmol) in 20 mL of anhydrous DCM was cooled to −10° C. Then MSCl (371mg, 3.24 mmol) was carefully added and the mixture was warmed to RT andstirred for 30 min. Then 10 mL of sat. NaHCO₃ was added and the mixturewas extracted with DCM (2×20 mL). The extract was dried over Na₂SO₄ andevaporated to give crude oil of mesylate. This oil was dissolved in 3 mLof anh. DMF. Then NaN₃ (351 mg, 5.4 mmol) was added and the mixture washeated at 80° C. for 2 h. Then 30 mL of water added and extracted with20 mL of EtOAc/hexane 1:1 mixture. The extract was dried over Na₂SO₄ andevaporated to give crude oil of azide, which was dissolved in 50 mL ofEtOAc, then Pd/C (150 mg of 10% Pd) was added and the mixture washydrogenated under hydrogen balloon for 1 h. The catalyst was removed byfiltration through celite, then purified by column (MeOH/EtOAc/NH₄OH5:93:2) to give (S)-2-(2-ethyl-phenyl)-1-methyl-ethylamine (328 mg, 74%)as pale oil. ESI-MS: m/z (MH⁺) 164.4. ¹H NMR (300 MHz, CDCl₃): δ 7.16(m, 4H), 3.16 (m, 1H), 2.52-2.78 (m, 4H), 1.30 (br., 2H), 1.22 (t,J=7.53 Hz, 3H), 1.14 (d, J=6.21 Hz, 3H).

(S)-2-(3,5-Difluoro-2-methyl-phenyl)-1-methyl-ethylamine

(S)-2-(3,5-Difluoro-2-methyl-phenyl)-1-methyl-ethylamine: A solution of(R)-1-(3,5-difluoro-2-methyl-phenyl)-propan-2-ol (500 mg, 2.7 mmol) andDIEA (0.94 mL, 5.4 mmol) in 20 mL of anhydrous DCM was cooled to −10° C.Then MsCl (371 mg, 3.24 mmol) was carefully added and the mixture waswarmed to RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was addedand the mixture was extracted with DCM (2×20 mL). The extract was driedover Na₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 3 mL of anh. DMF. Then NaN₃ (351 mg, 5.4 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil of azide, which wasdissolved in 20 mL of MeOH, then Pd/C (150 mg of 10% Pd) was added andthe mixture was hydrogenated under hydrogen balloon for 16 h. Thecatalyst was removed by filtration through celite, then purified bycolumn (MeOH/EtOAc/NH₄OH 5:93:2) to give(S)-2-(3,5-difluoro-2-methyl-phenyl)-1-methyl-ethylamine (197 mg, 39%)as pale oil. ESI-MS: m/z (MH⁺) 186.3. ¹H NMR (300 MHz, CDCl₃): δ 6.98(t, J=8.37 Hz, 1H), 6.73 (t, J=9.69 Hz, 1H), 3.14 (m, 1H), 2.46-2.69 (m,2H), 2.23 (s, 3H), 1.25 (br., 2H), 1.10 (d, J=6.42 Hz, 3H).

(S)-1-Methyl-2-(2,3,5,6-tetrafluoro-phenyl)-ethylamine

(S)-1-Methyl-2-(2,3,5,6-tetrafluoro-phenyl)-ethylamine: A solution of(R)-1-(2,3,5,6-tetrafluoro-phenyl)-propan-2-ol (1.12 g, 5.4 mmol) andDIEA (1.88 mL, 10.8 mmol) in 20 mL of anhydrous DCM was cooled to −10°C. Then MSCl (742 mg, 6.48 mmol) was carefully added and the mixture waswarmed to RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was addedand the mixture was extracted with DCM (2×20 mL). The extract was driedover Na₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 5 mL of anh. DMF. Then NaN₃ (702 mg, 10.8 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil of azide, which wasdissolved in 50 mL of EtOAc, then Pd/C (150 mg of 10% Pd) was added andthe mixture was hydrogenated under hydrogen balloon for 3 h. Thecatalyst was removed by filtration through celite, then purified bycolumn (MeOH/EtOAc/NH₄OH 5:93:2) to give(S)-1-methyl-2-(2,3,5,6-tetrafluoro-phenyl)-ethylamine (268 mg, 24%) asa white solid. ESI-MS: m/z (MH⁺) 208.3. ¹H NMR (300 MHz, DMSO-d₆): δ7.91 (br, 2H), 7.89 (m, 1H), 3.44 (m, 1H), 2.88-3.09 (m, 2H), 1.15 (d,J=6.60 Hz, 3H).

(S)-2-(2,5-Dimethoxy-phenyl)-1-methyl-ethylamine

(S)-2-(2,5-Dimethoxy-phenyl)-1-methyl-ethylamine: A solution of(R)-1-(2,5-dimethoxy-phenyl)-propan-2-ol (1.2 g, 5.4 mmol) and DIEA(1.88 mL, 10.8 mmol) in 20 mL of anhydrous DCM was cooled to −10° C.Then MsCl (742 mg, 6.48 mmol) was carefully added and the mixture waswarmed to RT and stirred for 30 min. Then 10 mL of sat. NaHCO₃ was addedand the mixture was extracted with DCM (2×20 mL). The extract was driedover Na₂SO₄ and evaporated to give crude oil of mesylate. This oil wasdissolved in 5 mL of anh. DMF. Then NaN₃ (702 mg, 10.8 mmol) was addedand the mixture was heated at 80° C. for 2 h. Then 30 mL of water addedand extracted with 20 mL of EtOAc/hexane 1:1 mixture. The extract wasdried over Na₂SO₄ and evaporated to give crude oil of azide, which wasdissolved in 50 mL of EtOAc, then Pd/C (150 mg of 10% Pd) was added andthe mixture was hydrogenated under hydrogen balloon for 3 h. Thecatalyst was removed by filtration through celite, the mixture wasevaporated and the crude residue was used directly in the next step.

To a cooled (−78° C.) solution of thiophene (10a) (3.18 g, 37.87 mmol)in THF (20.0 mL) was slowly added n-BuLi (15.15 mL, 2.5 M solution inhexane). After 30 minutes, a solution of (S)-(−)-propylene oxide (11a)(2.0 g, 34.43 mmol) in THF (10 mL) was added followed by BF3.Et2O (4.9g, 34.43 mmol). The resulting solution was slowly brought to roomtemperature and stirred for over night. The reaction was quenched withNH₄Cl solution (20 mL) and extracted with ether (3×50 mL). The organicextracts were dried and solvent was distilled off. The obtained crudeproduct was dissolved in DCM (50 mL) and DIPEA (6.67 g, 51.6 mmol) andcooled to 0° C. A solution of methanesulfonyl chloride (10.0 g, 87.3mmol) in DCM (4.93 g, 34.43 mmol) was added and resulting mixture wasstirred at room temperature for over night. The reaction mixture waswashed with water (3×30 mL), dried and concentrated to give crudecompound that was purified on silica gel column using 20% EtOAc/hexaneto afford (1S)-1-methyl-2-thien-2-ylethyl methanesulfonate (12a, 5.2 g,68%) ¹H NMR (CDCl₃) δ 1.48 (d, 3H, J=6.0 Hz), 2.71 (s, 3H), 3.05-3.22(m, 2H), 4.85-4.95 (m, 1H), 6.90-6.98 (m, 2H), 7.19 (d, 1H, J=3.0 Hz).

A mixture of (1S)-1-methyl-2-thien-2ylethyl methanesulfonate (12a) (2.5g, 11.34 mmol) and sodium azide (3.6 g, 56.73 mmol) in DMF (25 mL) wasstirred at 70° C. for over night. The reaction mixture was diluted withcold water (60 mL) and extracted with ethyl acetate (2×50 mL). Thecombined extract was washed with water (2×20 mL), dried and concentratedto get crude azide that was purified by silica gel column using 10%ethyl acetate/hexane to get pure azide (1.5 g, 78%). ¹H NMR (CDCl₃) δ1.21 (d, 3H, J=3.0 Hz), 2.91 (m, 2H), 3.60-3.75 (m, 1H), 6.86 (d, 1H,J=3.0 Hz), 6.95 (t, 1H, J=3.0 Hz), 7.13 (d, 1H, J=3.0 Hz). To a 0° C.cooled solution of SnCl₂ (91.2 g, 5.97 mmol) was added a solution ofazide (0.5 g, 2.9 mmol) in methanol (3 mL). After stirring at roomtemperature for 7 h, and solvent was removed under reduced pressure. Tothe residue were added DCM (20 mL) and saturated KOH solution (pH ˜12).The aqueous layer was extracted with DCM (3×20 mL). The combinedextracts were dried and concentrated at room temperature to get(1R)-1-methyl-2-thien-2-ylethylamine (13a, 320 mg, 76%). ¹H NMR (CDCl₃)δ 1.03 (d, 3H, J=6.0 Hz), 2.73 (ABq, 1H, J=6.0, 15.0 Hz), 2.91 (ABq, 1H,J=6.0, 15.0 Hz), 3.01-3.23 (m, 1H), 6.83 (d, 1H, J=3.0 Hz), 6.94 (t, 1H,J=3.0 Hz), 7.15 (d, 1H, J=3.0 Hz).

The following amines were synthesized using this procedure, unlessotherwise noted.

(1S)-1-methyl-2-thien-2-ylethylamine hydrochloride (13b) was preparedfrom (R)-(+)-propylene oxide and converted as hydrochloride salt. (19.8g, 39%, 4 steps). ¹H NMR (CDCl₃) δ 1.17 (d, 3H, J=6.0 Hz), 2.93 (ABq,1H, J=6.0, 15.0 Hz), 3.20 (ABq, 1H, J=6.0, 15.0 Hz), 3.34-3.42 (m, 1H),6.97-7.02 (m, 2H), 7.43 (d, 1H, J=6.0 Hz), 8.19 (bs, 1H, 3H).

(1S)-2-(3-chlorothien-2-yl)-1-methylethylamine (13c)

(1S)-2-(3-chlorothien-2-yl)-1-methylethylamine (13c): Note: BuLi wasadded to a solution of 3-chlorothiophene at 0° C.

(750 mg, 50.6% four steps). ¹H NMR (CDCl₃) δ 1.15 (d, 3H, J=9.0 Hz),2.75 (ABq, 1H, J=6.0, 15.0 Hz), 2.87 (ABq, 1H, J=6.0, 15.0 Hz),3.17-3.27 (m, 1H), 6.88 (d, 1H, J=3.0 Hz), 7.13 (d, 1H, J=3.0 Hz).

(1S)-2-(3-methoxythien-2-yl)-1-methylethylamine (13d)

(1S)-2-(3-methoxythien-2-yl)-1-methylethylamine (13d). Note: BuLi wasadded to a solution of 3-methoxythiophene at 0° C.

(400 mg, 53%) ¹H NMR (CDCl₃) δ 1.16 (d, 3H, J=6.0 Hz), 2.60-2.82 (m,2H), 3.10-3.25 (m, 1H), 3.82 (s, 3H), 6.82 (d, 1H, J=3.0 Hz), 7.03 (d,1H, J=3.0 Hz).

(1S)-2-(3-methylthien-2-yl)-1-methylethylamine (13e)

(1S)-2-(3-methylthien-2-yl)-1-methylethylamine (13e). Note n-BuLi wasadded to the solution of 2-bromo-3-methylthiophene at 21-25° C.

(560 mg, 62%) ¹H NMR (CDCl₃) δ 1.27 (d, 3H, J=6.0 Hz), 2.18 (s, 3H),2.65-2.84 (m, 2H), 3.13-3.45 (m, 1H), 6.80 (d, 1H, J=3.0 Hz), 7.06 (d,1H, J=3.0 Hz).

(1S)-2-(2-furyl)-1-methylethylamine (13f)

(1S)-2-(2-furyl)-1-methylethylamine (13f) was prepared from freshlydistilled furan.

(500 mg, 27%). ¹H NMR (CDCl₃) δ 1.14 (d, 3H, J=6.0 Hz), 2.53-2.78 (m,2H), 3.14-3.30 (m, 1H), 6.07 (d, 1H, J=3.0 Hz), 7.30 (d, 1H, J=3.0 Hz).

(S)-1-methyl-2-o-tolyl-ethylamine

(S)-1-methyl-2-o-tolyl-ethylamine (13g) was prepared from2-bromotoluene. (600 mg, 65%) ¹H NMR (CDCl₃) δ 1.14 (d, 3H, J=6.0 Hz),2.33 (s, 3H), 2.54-2.77 (m, 2H), 3.14-3.25 (m, 1H), 7.07-7.18 (m, 4H).

To a cooled (−78° C.) solution of 2,6-dichlorobromobenzene (14a) (970mg, 4.3 mmol) in THF (10.0 mL) was slowly added n-BuLi (1.75 mL, 2.5 Msolution in hexane). After 20 minutes, a solution of (R)-(+)-propyleneoxide (11b) (250 mg, 4.3 mmol) was added. The resulting solution wasslowly brought to room temperature and stirred for 7 h. The reaction wascooled to 0° C. and methanesulfonyl chloride (0.5 g, 4.3 mmol) wasslowly added and stirred at room temperature for over night. Thereaction mixture was diluted with water (15 mL) and extracted with ethylacetate (3×10 mL). The extracts were dried and concentrated to get crudeproduct (15a) that was stirred with sodium azide (1.4 g, 21.5 mmol) inDMF (15 mL) at 70° C. for 3 h. The reaction mixture was diluted withcold water (30 mL) and extracted with ethyl acetate (2×25 mL). Thecombined extract was washed with water (2×20 mL), dried and concentratedto get crude azide that was purified by silica gel column using 10%ethyl acetate/hexane to get pure azide. To a 0° C. cooled solution ofSnCl₂ (1.5 g, 7.9 mmol) was added a solution of crude azide in methanol(3 mL). After stirring at room temperature for 7 h, and solvent wasremoved under reduced pressure. To the residue were added DCM (20 mL)and saturated KOH solution (pH ˜12). The aqueous layer was extractedwith DCM (3×20 mL). The combined extracts were dried and concentrated atroom temperature to get crude(1S)-2-(2,6-dichloro-phenyl)-1-methyl-1-ethylamine (16a) (500 mg) ESI-MSm/z 204.6 (M⁺+1). The obtained amine was used for next reaction withoutfurther purification.

The following amines were synthesized using the same procedure unlessotherwise noted.

(1S)-2-(2,5-dichloro-phenyl)-1-methyl-1-ethylamine

(1S)-2-(2,5-dichloro-phenyl)-1-methyl-1-ethylamine (16b) (600 mg) ESI-MSm/z 204.6 (M⁺+1).

(1S)-2-(2,3-dichloro-phenyl)-1-methyl-1-ethylamine

(1S)-2-(2,3-dichloro-phenyl)-1-methyl-1-ethylamine (16C) (450 mg) ESI-MSm/z 204.6 (M⁺+1).

(1S)-2-(2,6-dimethyl-phenyl)-1-methyl-1-ethylamine

(1S)-2-(2,6-dimethyl-phenyl)-1-methyl-1-ethylamine (16d) (400 mg) ESI-MSm/z 164.3 (M⁺+1).

(1S)-2-(5-fluoro-2-methyl-phenyl)-1-methyl-1-ethylamine

(1S)-2-(5-fluoro-2-methyl-phenyl)-1-methyl-1-ethylamine (16e) (600 mg)ESI-MS m/z 168.3 (M⁺).

(1S)-2-(4-fluoro-2-methyl-phenyl)-1-methyl-1-ethylamine

(1S)-2-(4-fluoro-2-methyl-phenyl)-1-methyl-1-ethylamine (161) (600 mg)ESI-MS m/z 168.3 (M⁺).

(1S)-2-(3-fluoro-2-methyl-phenyl)-1-methyl-1-ethylamine

(1S)-2-(3-fluoro-2-methyl-phenyl)-1-methyl-1-ethylamine (16g) (600 mg)ESI-MS m/z 168.3 (M⁺).

A mixture of2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onedihydrochloride (17) (2.2 g, 4.9 mmol),(1S)-1-methyl-2-thien-2-ylethylamine hydrochloride (13b) (870 mg, 4.9mmol) and Et₃N (3.44 mL, 24.5 mmol) in EtOH (20 mL) was heated at 100°C. for 12 h. The mixture was concentrated, diluted with water (20 mL)and extracted with CHCl₃ (5×20 mL) the combined organic layer was dried,concentrated to a residue that was purified on silica gel column using10% NH4OH/methanol in CH₂Cl₂ to get pure2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one(18a) (1.2 g, 51%). ¹H NMR (DMSO-d₆) δ 1.33 (d, 3H, J=3.0 Hz), 1.55-1.85(m, 6H), 2.3-2.45 9 m, 6H), 3.15-3.25− (m, 2H), 3.56 (t, 2H, J=6.0 Hz),3.95-4.15 (m, 1H), 4.51 (s, 2H), 6.15 (d, 1H, J=9.0 Hz), 6.91-6.96 (m,1H), 7.05 (t, 1H, J=3.0 Hz), 7.31-7.36 (m, 2H), 7.66 (s, 0.5H), 7.79 (d,1H, J=3.0 Hz), 7.93 (s, 0.5H), 11.14 (d, 1H, J=9.0 Hz), 11.24 (bs, 1H).ESI-MS m/z 517.67 (M⁺+1).

2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one

2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one(18d) was prepared from (1S)-2-(3-chlorothien-2-yl)-1-methylethylamine(13c) and2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onedihydrochloride. ESI-MS m/z 551.5 (M⁺) and 553.0 (M⁺+2).

2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one

2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one(18e) was prepared from (S)-1-methyl-2-o-tolyl-ethylamine (13g) and2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onedihydrochloride (14). ESI-MS m/z 525 (M⁺+1).

2-[4-((S)-2-furan-2-yl-1-methyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one

2-[4-((S)-2-furan-2-yl-1-methyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one(18f) was prepared from (1S)-2-(2-furyl)-1-methylethylamine (131) and2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onedihydrochloride (14). ESI-MS m/z 501.4 (M⁺+1).

Crude2-[4-((S)-1-methyl-2-(3-methylthiophen-2-yl)-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5,7-dione(19a) (50 mg) was mixed with zinc dust (123 mg) in AcOH (2 mL) andheated at 100° C. for 2.5 h. The mixture was cooled, filtered throughcelite and solid was washed with 1:1 MeOH/CH₂Cl₂ (5 mL). The filtratewas concentrated and the residue was passed through small silica gelcolumn (10% NH4OH in MeOH/CH₂Cl₂ (1:9). Column fractions wereconcentrated and obtained compound was subjected to HPLC purification toafford2-{4-[(S)-1-methyl-2-(3-methyl-thiophen-2-yl)-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt (20a). (10 mg). ESI-MS m/z 517.5 (M⁺+1).

In a similar manner the following compounds were synthesized.

2-{4-[(S)-1-methyl-2-(3-chloro-thiophen-2-yl)-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt (20b)

(11 mg). ESI-MS m/z 537.5 (M⁺).

2-{4-[(S)-1-methyl-2-(3-trifluoromethyl-thiophen-2-yl)-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt (20c)

(11 mg). ESI-MS m/z 571.5 (M⁺+1).

2-{4-[(S)-1-methyl-2-otolyl-ethylamino-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt (20d)

(15 mg). ESI-MS m/z 511.5 (M⁺+1).

2-[4-((S)-2-furan-2yl-1-methyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(2-pyrrolidin-1-yl-ethyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-onetrifluoroacetic acid salt (20e)

15 mg). ESI-MS m/z 487.1 (M⁺+1).

A mixture containing phthalimide (1; 2 g, 9.7 mmol, 1.0 eq.),2-pyrrolidin-1-ylethanamine (2a, 1.1 g, 9.7 mmol, 1.0 eq.) and imidazole0.17 g, 2.43 mmol, 0.25 eq.) in dioxane (40 mL) was heated in a cappedvial at 110° C. for 14 h. Additional 0.25 eq. of imidazole was added andreaction heated for 24 h. The mixture was cooled to room temperature andconcentrated in vacuo to a solid which was used as such in the nextstep.

The following compounds were prepared using either of the above methods:

Synthesis of Phthalimide Halopyridones Method A2-(4-Iodo-2-methoxypyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(6b)

Pd/C (250 mg) was added to a solution of crude 3b in MeOH/AcOH (100 mL/5mL) and hydrogenated for 5 h. The mixture was filtered through Celiteand the filtrate was treated with 4-iodo-2-methoxynicotinaldehyde (3.2g, 12.07 mmol) and stirred at ambient temperature open to air for 12 hand at 80° C. for 5 h. The reaction mixture was cooled to ambienttemperature and concentrated in vacuo to dryness. Purification by flashchromatography gave the title phthalimide 6b as a solid (2.02 g, 32%over 4 steps). ¹H NMR (MeOD): δ 8.15 (s, 2H), 8.01-8.08 (t, J=3 Hz 1H),7.64 (t, J=3 Hz, 1H), 3.89-3.78 (m, 2H), 3.41-3.22 (m, 2H), 2.95-2.81(m, 6H), 2.15-1.82 (m, 7H). ESMS (m/z) 532 (M+H)⁺.

2-(4-Halo-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionedihydrochloride (7b)

A mixture of concentrated HCl (6 mL) and 2-methoxypyridine (1.97 g, 33.7mmol) in 45 mL of dioxane was stirred at ambient temperature protectedfrom light for 30 h. THF (25 mL) was added to the reaction mixture andthe solid was isolated by filtration, washed with Et₂O (4×15 mL), driedat 45° C. in a vacuum oven to afford the title compound as a lightchocolate colored solid (1.82 g). ¹H NMR (MeOH-d₄): δ 12.74 (br s, 1H),10.60 (br s, 1H), 8.14 (s, 2H), 7.73 (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz,1H), 3.72-3.64 (m, 1H), 3.51-3.43 (m, 1H), 3.21-3.15 (m, 1H), 2.99-2.93(m, 1H), 2.07-1.82 (m, 3H). ESMS (m/z) 426.1 (M+H)⁺ for X═Cl and 518.2(M+H)⁺ for X═I.

Synthesis of Phthalimido Halopyridones Method B

Step 1:

NaH (2.05 g, 60 wt % dispersion in oil, 5.13 mmol, 1.06 eq.) was addedportion wise to a solution of the phthalimide (10.0 g, 48.3 mmol, 1.0eq.) in degassed DMF (50 mL) and heated at 60° C. for 45 min. Themixture was cooled to room temperature and stirred overnight. Then, asolution of dibromoethane (18.1 g, 96.6 mmol) in acetone (50 mL) wasadded drop wise. The cake was broken up and thick slurry was refluxedovernight. The reaction mixture was cooled to room temperature andfiltered. The filtrate was concentrated in vacuo to a residual oil. Thefilter cake was washed with MeOH and filtered into the residual oil.Additional MeOH was added and the yellow powder obtained was isolatedand washed with hexanes to afford 10.14 g (67%) of the desired product.The filtrate cake was taken up in EtOAc (100 mL) and washed with water(50 mL). The aqueous layer was back extracted with EtOAc (50 mL). Theorganic extracts were combined, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford a yellow solid (2.11 g, 14%) afterdrying in an oven under high vacuum. Overall yield (12.26 g, 81%). ¹HNMR (DMSO-d₆) 8.45 (br s, 2H) 8.35 (s, 1H), 7.48 (s, 1H), 3.96 (t,J=6.33 Hz, 2H), 3.70 (t, J=6.33 Hz, 2H).

Step 2:

A mixture of the bromophthalimide (1.0 g, 3.2 mmol), AcOH (10 drops) inMeOH (15 mL) was hydrogenated at atmospheric pressure and ambienttemperature for 3 h. The mixture was filtered through Celite, Celite waswashed well with MeOH, and the filtrate was concentrated in vacuo toafford a residual solid (840 mg; 92%). ¹H NMR (CDCl₃) 7.11 (s, 2H), 4.02(t, J=6.72 Hz, 2H), 3.86 (br s, 4H), 3.57 (t, J=6.72 Hz, 2H)

Step 3:

Aldehyde (508 mg, 2.96 mmol, 1.0 eq.) was added to a heterogeneousmixture of the diaminophthalimide (840 mg, 2.96 mmol, 1.0 eq.) inMeOH/AcOH (3/1; 40 mL) and stirred at ambient temperature for 48 h. Thereaction mixture was concentrated in vacuo to a residual solid andpurified by flash chromatography (R_(f)=0.30; 20% EtOAc/DCM) to isolatefractions corresponding to the desired product (1.25 g, 97%, 84% pure).¹H NMR (CDCl₃) 10.90 (br s, 1H), 8.18 (d, J=5.5 Hz, 1H), 7.15 (d, J=5.5Hz, 1H), 4.15 (t, J=6.7 Hz, 2H), 3.65 (t, J=6.7 Hz, 2H). ESMS (m/z) 435.

Step 4:

Bromoethylphthalimide (1 eq.) and the secondary amine (3.0 eq.) [Note:1.2 eq. of powdered K₂CO₃ was added if secondary amine was HCl salts asin preparation of 5j and 5k) in degassed, anhydrous DMF (0.13 Msolution) and heated in capped vial at 75-80° C. for 6-48 h. The desiredproducts were purified by flash chromatography to afford products asshown below.

Analytical data for2-(4-Chloro-2-methoxypyridin-3-yl)-6-{(2-[(2S)-2-methylpyrrolidin-1-yl]ethyl}imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(6i): ¹H NMR (CDCl₃) 8.28 (br s, 1H), 8.17 (d, J=5.5 Hz, 1H), 8.02 (brs, 1H), 7.14 (d, J=5.5 Hz, 1H), 4.01 (s, 3H), 3.41-3.09 (m, 2H),2.47-2.19 (m, 3H), 1.91-1.78 (m, 1H), 1.65-1.52 (m, 1H), 1.45-1.29 (m,1H), 1.25 (br s, 1H), 1.19-1.17 (m, 1H), 1.03 (d, J=3.3 Hz, 3H)0.91-0.72 (m, 1H). ESMS (m/z) 440.91.

Analytical data for2-(4-Chloro-2-methoxypyridin-3-yl)-6-[2-(1,1-dioxidothiomorpholin-4-yl)ethyl]imidazo[4,5-f]isoindole-5,7(1H,6H)-dione.¹H NMR (MeOH-d₄) 8.32 (d, J=5.6 Hz, 1H), 8.14 (s, 2H), 7.29 (d, J=5.6Hz, 1H), 4.05-3.94 (m, 5H), 3.53-3.37 (m, 4H), 3.29-3.10 (m, 6H). ESMS(m/z) 490.3.

Step 5:

The crude product from Step 4 above was dissolved in dioxane/con HCl(5/1) and stirred at ambient temperature overnight. The reaction mixturewas concentrated in vacuo to dryness, azeotroped with EtOH (2×) toobtain the monoHCl salts 5j, 5k, and 5l as a powder. These were used inthe next steps as such.

Synthesis of Lactam-Containing Chloropyridones

Step 1:

Tin powder (1.96 g, 16.5 mmol, 10.0 eq.) was added to a solution ofaminophthalimide (550 mg, 1.65 mmol) in EtOH (7 mL)/con HCl (1.7 mL) andrefluxed for 24 h. Another batch of tin powder (1.96 g, 16.5 mmol) andcon Hcl (1.7 mL) were added and reflux continued for 15 h. The reactionmixture was decanted to remove tin, and concentrated in vacuo to aresidue. The residue was dissolved in MeOH and conc. aq. NH₄OH was addeduntil no more precipitation was observed. The reaction mixture wasfiltered and silica gel was added to the filtrate and concentrated invacuo. The residue was adsorbed on silica gel and purified by flashchromatography [10% (5% aq. NH₄OH/MeOH)/DCM; R_(f)=0.32] to afford thedesired product as a thick yellow oil (314 mg, 66%).

Step 2:

A solution of the aldehyde (189 mg, 1.1 mmol, 1.0 eq.) in MeOH (10 mL)was added drop wise to a 0-5° C. solution of the lactam (0.31 g, 1.1mmol; from step 1) in MeOH (10 mL) and stirred at room temperature for14 h and at 50° C. for 1 d. The reaction mixture was filtered throughCelite, and the filtrate was concentrated in vacuo to a residue andpurified by flash chromatography [10% (5% aq. NH₄OH/MeOH)/DCM;R_(f)=0.40) to isolate fractions corresponding to the desired product.The isolated product was used as such in the next step.

Step 3:

Con HCl (0.8 mL) was added to a solution of the product from step 2 (225mg, 0.51 mmol) in dioxane (3 mL) and stirred at ambient temperatureovernight and at 60° C. for 2 h. The reaction mixture was concentratedin vacuo to dryness to afford 279 mg of the desired product as a greysolid. ESMS (m/z) 426.4. This was used as such in the next steps.

In a similar fashion was synthesized2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

Synthesis of Amino-Substituted Phthalimides

The synthesis of amino-substituted tricyclic phthalimido-derivatives wasperformed using general methodology described in WO 2008021369 A220080221.

The following compounds were synthesized by application of the abovemethodology.

2-(4-{[(1S)-1-Methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(13b) ESMS (m/z) 517.5 (M+H)⁺; Yield (32%)

2-(4-{[1-Methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(15b) ESMS (m/z) 613.5 (M+H)⁺ 531.3; Yield (64%); Purity 99%

2-(4-{[1-Methyl-2-(3-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(19b) ESMS (m/z) 531.5 (M+H⁺); Yield (66%)

2-(2-oxo-4-{[1-(2-thienylmethyl)propyl]amino}-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(20b) ESMS (m/z) 545.5 (M+H⁺); Yield (77%). [Reference for thienylamine: Gilsdorf, R. T.; Nord, F. F. J. Org. Chem. V15, No. 4, 1950,807-811]

2-(4-{[2-(3,5-Dimethylisoxazol-4-yl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(21b) ESMS (m/z) 544.5 (M+H⁺); Yield (40%); Purity 99%. [The isoxazolylderived primary amine was synthesized as in Gilsdorf, R. T.; Nord, F. F.J. Org. Chem. V15, No. 4, 1950, 807-811]

2-(4-{[(1R)-1-methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(22b) ESMS (m/z) 531.3 (M+H⁺); Yield (81%); Purity 99%

2-(4-{[2-(4-fluorophenyl)-1,1-dimethylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(24b) ESMS (m/z) 557.5 (M+H⁺); Yield (27%); Purity 96%

2-(4-{Methyl[1-methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(25b) ESMS (m/z) 545 (M+H⁺); Yield (74%); Purity 95%. [The thienyl aminewas synthesized as in J. Am. Chem. Soc. V64, No. 3, 1942, 477-479]

2-(4-{[2-(5-Chloro-2-thienyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(26b) ESMS (m/z) 565.3 (M+H⁺); Yield (52%); Purity 99%. Thienyl aminesynthesized as in J. Org. Chem. V15, No. 4, 1950, 807-811]

2-(4-{[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione(27b) ESMS (m/z) 541.3 (M+H⁺); Yield (60%); Purity 99%

Synthesis of Amino-Substituted Lactams Method A

Zn (246 mg, 3.8 g atoms, 23.3 eq.) was added to a solution of thephthalimide 23b (95 mg, 0.163 mmol) and heated at 120° C. for 2 h.Reaction mixture was cooled to ambient temperature and the mixture wasfiltered through Celite. Celite was washed with MeOH (3×10 mL) and thefiltrate was concentrated in vacuo and azeotroped with toluene (3×15mL). Flash chromatography purification of the resultant residue [10% (5%aq. NH₄OH/MeOH)/DCM] afforded the desired compound as a cream solid (41mg, 44%). R_(f)=0.40; more polar of the two UV and fluorescent spots ofthe crude material. ¹H NMR (DMSO-d₆): δ 12.62 (s, 1H), 11.27 (br s, 1H),11.06 and 10.75 (br singlets, 1H), 7.93 and 7.87 (s, 1H), 7.1629 (br s,1H), 6.99-6.92 (m, 1H), 6.76 (d, J=7.1 Hz, 1H), 6.07 (br s, 1H),4.55-4.35 (m, 2H), 4.18-4.07 (m, 2H), 3.80-3.51 (m, 2H), 3.21-3.05 (brs, 2H), 2.71-2.59 (m, 2H), 2.58-2.38 (m, 5H), 2.29-2.59 (m, 4H),2.40-1.98 (m, 5H), 1.98-1.78 (m, 3H), 1.31-1.05 (m, 3H). ESMS (m/z)571.5 (M+H)⁺.

Synthesis of Amine-Substituted Lactams Method B

Et₃N 0.15 mL, 1.1 mmol, 5.0 eq.) was added to a mixture containing2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-methyl-3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(100 mg, 0.22 mmol) and (2S)-1-(3-methyl-2-thienyl)propan-2-amine (38mg, 0.24 mmol) in EtOH (1 mL) and heated in a capped vial at 100° C. for14 h. The mixture was concentrated in vacuo and purified by prep HPLC toafford fractions corresponding to the desired product (45 mg, 38%). ¹HNMR (MeOH-d₄) 7.96 (s, 1H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.08(d, J=4.41 Hz, 1H), 6.73 (d, J=5.13 Hz, 1H), 6.15 (d, J=7.5 Hz, 1H),4.67 (s, 2H), 4.19-4.07 (m, 1H), 3.86-3.77 (m, 3H), 3.68-3.56 (m, 1H),3.23-3.02 (m, 6H), 2.54-2.41 (m, 1H), 2.26-2.02 (m, 7H), 1.46 (d, J=6.3Hz, 3H), 1.17 (d, J=6.6 Hz, 3H). ESMS (m/z) 545.3 (M+H)⁺.

The following lactams were obtained using Method A unless otherwisespecified

2-(4-{[1-methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one

(32b) ESMS (m/z) 613.5 (M+H)⁺ 517.3; Yield (75%)

2-(4-{[1-methyl-2-(3-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(R/S-36b) ESMS (m/z) 517.5 (M+H⁺); Yield (72%)

2-(2-Oxo-4-{[1-(2-thienylmethyl)propyl]amino}-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(37b) ESMS (m/z) 531.5 (M+H⁺); Yield (83%)

2-(4-{[2-(3,5-Dimethylisoxazol-4-yl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(38b) ESMS (m/z) 530.5 (M+H⁺); Yield (38%); Purity 91%

2-(4-{[(1R)-1-Methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one[(R)-36b] ESMS (m/z) 531.3 (M+H⁺); Yield (76%); Purity 100%

2-(4-{[2-(4-Fluorophenyl)-1,1-dimethylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(40b) ESMS (m/z) 543.5 (M+H⁺); Yield (100%); Purity 96%

2-(4-{Methyl[1-methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(41b) ESMS (m/z) 531 (M+H⁺); Yield (49%); Purity 95%

2-(4-{[2-(5-Chloro-2-thienyl)-1-methylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(42b) ESMS (m/z) 551.3 (M+H⁺); Yield (63%); Purity 99%

2-(4-{[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-pyrrolidin-1-ylpropyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(43b) ESMS (m/z) 551.3 (M+H⁺); Yield (63%); Purity 99%

6-[2-(1,1-Dioxidothiomorpholin-4-yl)ethyl]-2-(4-{[(1S)-1-methyl-2-(3-methyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one(44j) ESMS (m/z) 581.3 (M+H⁺); Yield (63%); Purity 99%

6-{[(2S)-1-Ethylpyrrolidin-2-yl]methyl}-2-(4-{[(1S)-1-methyl-2-(3-methyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(45g) ESMS (m/z) 531.3 (M+H⁺); Yield (22%); Purity 99%

6-{[(2R)-1-Ethylpyrrolidin-2-yl]methyl}-2-(4-{[(1S)-1-methyl-2-(3-methyl-2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(45h) [Method B] ESMS (m/z) 531.3 (M+H⁺); Yield (20%); Purity 99%

2-(4-{[(1S)-1-Methyl-2-(2-thienyl)ethyl]amino}-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one(48a) ESMS (m/z) 503.5 (M+H⁺); Yield (48%); purity 100%

Preparation of 5,6-diaminoisoindolin-1-one

A solution of 5-Amino-6-nitroisoindoline-1,3-dione (1.0 g, 4.83 mmol)and tin powder (5.8 g, 48.3 mmol) in EtOH (30 mL) was heated at 90° C.for 4 h. The reaction mixture was cooled to RT, filtered theprecipitated solid, washed with EtOH (10 mL) and dried to afford5,6-diaminoisoindolin-1-one (0.75 g, 95%) as a yellow solid. LCMS: 164(M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 4.25 (s, 2H); 7.93 (s, 1H), 7.41 (s,1H); 8.22 (s, 1H); 9.0 (br.s, 4H).

Preparation of(S)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

Yield: 40 mg (10%)

LCMS: 432 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.35 (d, J=3.0 Hz, 1H);2.48 (s, 3H); 3.02 (m, 2H); 4.17 (m, 1H); 4.55 (s, 2H); 6.15 (m, 1H);6.95 (m, 1H); 7.1-7.4 (m, 3H); 7.70-8.05 (m, 2H); 8.40 (s, 1H);11.00-11.23 (m, 2H).

Preparation of5-Amino-2-(2-(dimethylamino)ethyl)-6-nitroisoindoline-1,3-dione

To a suspension of 5-Amino-6-nitroisoindoline-1,3-dione (5.0 g, 24.15mmol) in Dowtherm (75 mL) were added imidazole (1.64 g, 24.15 mmol) andN¹,N¹-dimethylethane-1,2-diamine (3.16 mL, 24.15 mmol) and the resultingmixture was heated at 150° C. for overnight. The reaction mixture wascooled to RT, was added ether (100 mL). The yellow precipitate wascollected by filtration and washed with ether (2×50 mL) and dried toafford 5-Amino-2-(2-(dimethylamino)ethyl)-6-nitroisoindoline-1,3-dione(6.4 g, 95%) as a yellow solid.

LCMS: 279 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 2.21 (s, 6H); 2.50 (t,2H), 3.65 (t, 2H); 7.55 (s, 1H); 8.31 (s, 1H); 8.40 (br.s, 2H).

Preparation of5,6-Diamino-2-(2-(dimethylamino)ethyl)isoindoline-1,3-dione

Following the general procedure for hydrogenation in the preparation ofanalogs, 5,6-diamino-2-(2-(dimethylamino)ethyl)isoindoline-1,3-dione wasisolated in quantitative yield (5.7 g, 100%).

LCMS: 249 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 2.14 (s, 6H); 2.39 (t,2H); 3.51 (t, 2H); 5.54 (br.s, 4H); 6.85 (s, 2H).

Preparation of2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dionehydrochloride

Yield: 8.0 g from 5.7 g of diamine (82%).

LCMS: 386 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 2.83 (br.s, 6H); 3.35 (t,2H); 4.00 (m, 2H); 6.45 (d, J=6.0 Hz, 1H); 6.8 (br.s, 3H); 7.81 (d,J=6.0 Hz, 1H); 8.22 (s, 2H); 10.8 (br.s, 1H).

Preparation of(S)-6-(2-(dimethylamino)ethyl)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

Yield: 45 mg (38%).

LCMS: 503 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.34 (d, J=3.0 Hz, 3H);2.19 (s, 6H); 2.35 (s, 3H); 2.50 (m, 2H); 2.99 (t, 2H); 3.69 (t, 2H);4.17 (m, 1H); 6.14 (d, J=6.0 Hz, 1H); 6.84-6.89 (m, 1H); 7.10-7.31 (m,3H); 7.94 (s, 1H); 8.06 (s, 1H); 10.87 (d, J=6.0 Hz, 1H); 11.28 (br.s,1H).

Preparation of(S)-6-(2-(dimethylamino)ethyl)-2-(4-(1-(5-fluoro-2-methoxyphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 519 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (d, J=3.0 Hz, 3H);2.20 (s, 6H); 2.76-2.83 (m, 1H); 2.86-3.07 (m, 1H); 3.62-3.64 (m, 2H);3.80 (s, 3H); 4.02-4.10 (m, 1H); 4.53 (s, 2H); 6.23 (d, J=9.0 Hz, 1H);6.90-7.40 (m, 4H); 7.65-7.94 (m, 2H); 10.97-11.20 (2 br.s, 2H).

Preparation of(S)-6-(2-(dimethylamino)ethyl)-2-(4-(1-(2-methyl-5-(trifluoromethyl)phenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 553 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (d, J=3.0 Hz, 3H);2.20 (s, 6H); 2.50 (s, 3H); 2.96-2.99 (m, 2H); 3.62-3.64 (m, 2H); 4.18(s, 1H); 4.53 (s, 2H); 6.18 (d, J=9.0 Hz, 1H); 7.10-7.40 (m, 3H);7.65-7.94 (m, 3H); 10.97-11.20 (2 br.s, 2H); 13.10 (s, 1H)

Preparation of(S)-6-(2-(dimethylamino)ethyl)-2-(2-oxo-4-(1-(2,3,5-trifluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 525 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (d, J=3.0 Hz, 3H);2.20 (s, 6H); 2.96-2.99 (m, 2H); 3.62-3.64 (m, 2H); 4.18 (s, 1H); 4.53(s, 2H); 6.18 (d, J=9.0 Hz, 1H); 7.10-7.40 (m, 3H); 7.65-7.94 (m, 2H);10.97-11.20 (2 br.s, 2H); 13.10 (s, 1H).

Preparation of(S)-2-(4-(1-(3,4-difluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 521 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.34 (d, J=3.0 Hz, 3H);2.19 (s, 6H); 2.35 (s, 3H); 2.50 (m, 2H); 2.99 (t, 2H); 3.69 (t, 2H);4.17 (m, 1H); 6.14 (d, J=6.0 Hz, 1H); 6.84-6.89 (m, 1H); 7.10-7.31 (m,2H); 7.94 (s, 1H); 8.06 (s, 1H); 10.87 (d, J=6.0 Hz, 1H); 11.28 (br.s,1H); 13.50 (s, 1H).

Preparation of(S)-2-(4-(1-(3,5-difluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 521 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (d, J=3.0 Hz, 3H);2.01 (br.s, 4H); 2.19 (s, 6H); 2.50 (s, 3H); 2.80-2.99 (m, 2H); 3.69 (t,2H); 4.17 (m, 1H); 6.14 (d, J=6.0 Hz, 1H); 6.84-6.89 (m, 1H); 7.10-7.31(m, 2H); 7.94 (s, 1H); 8.06 (s, 1H); 10.87 (d, J=6.0 Hz, 1H); 11.28(br.s, 1H); 13.50 (s, 1H).

Preparation of(S)-2-(4-(1-(5-fluoro-2-methoxyphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 545 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (m, 3H); 1.79-1.82(m, 4H); 2.60-2.70 (m, 4H); 2.76-2.83 (m, 1H); 2.86-3.07 (m, 1H);3.62-3.64 (m, 2H); 3.80 (s, 3H); 4.02-4.10 (m, 1H); 4.53 (s, 2H); 6.23(d, J=9.0 Hz, 1H); 6.90-7.40 (m, 4H); 7.65-7.94 (m, 2H); 11.20 (2 br.s,2H); 13.00 (s, 1H).

Preparation of(5)-2-(2-oxo-4-(1-(2,3,5-trifluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 551 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (m, 3H); 1.79-1.82(m, 4H); 2.60-2.70 (m, 4H); 2.76-2.83 (m, 1H); 2.86-3.07 (m, 1H);3.62-3.64 (m, 2H); 3.80 (s, 3H); 4.02-4.10 (m, 1H); 4.53 (s, 2H); 6.23(d, J=9.0 Hz, 1H); 6.90-7.40 (m, 3H); 7.65-7.94 (m, 2H); 11.20 (2 br.s,2H); 13.00 (s, 1H).

Preparation of(S)-2-(4-(1-(5-(dimethylamino)-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 554 (M+1).

Preparation of(S)-2-(4-(1-(2-methyl-5-(trifluoromethyl)phenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

Preparation of(S)-2-(4-(1-(2-fluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 515 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (m, 3H); 1.69 (m, 4H); 2.60-2.70 (m,4H); 2.73 (m, 2H); 3.02-3.11 (m, 2H); 3.66-3.69 (m, 2H); 4.08-4.11 (m,1H); 4.55 (s, 2H); 6.16 (d, J=9.0 Hz, 1H); 7.01-7.40 (m, 4H); 7.65-7.94(m, 3H); 11.11, 11.20 (2 br.s, 2H); 13.00 (s, 1H).

Preparation of(S)-2-(4-(1-(2-chlorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 531 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (m, 3H); 1.69 (m, 4H); 2.60-2.70 (m,4H); 2.73 (m, 2H); 3.02-3.11 (m, 2H); 3.66-3.69 (m, 2H); 4.08-4.11 (m,1H); 4.55 (s, 2H); 6.16 (d, J=9.0 Hz, 1H); 7.01-7.40 (m, 4H); 7.65-7.94(m, 3H); 11.11, 11.20 (2 br.s, 2H); 13.00 (s, 1H).

Preparation of(S)-2-(4-(1-(3,4-difluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 547 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (m, 3H); 1.79-1.82 (m, 4H); 2.60-2.70(m, 4H); 2.76-2.83 (m, 1H); 2.86-3.07 (m, 1H); 3.62-3.64 (m, 2H); 3.80(s, 3H); 4.02-4.10 (m, 1H); 4.53 (s, 2H); 6.23 (d, J=9.0 Hz, 1H);6.90-7.40 (m, 3H); 7.65-7.94 (m, 2H); 11.20 (2 br.s, 2H); 13.00 (s, 1H).

Preparation of(S)-2-(4-(1-(2,5-dimethoxyphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 557 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.27 (d, J=6.0 Hz, 3H); 1.73 (br.s, 4H);2.65-2.80 (m, 3H); 3.00-3.04 (m, 1H); 3.39-3.57 (m, 3H); 3.61 (s, 3H);3.63-3.69 (m, 3H); 3.73 (s, 3H); 3.95-4.09 (m, 1H); 4.55 (d, J=3.0 Hz,2H); 6.25 (d, J=6.0 Hz, 2H); 6.87-6.93 (m, 3H); 7.38 (d, 1H); 7.65-7.99(m, 2H); 11.10 (m, 2H); 13.50 (s, 1H).

Preparation of(S)-2-(4-(1-(5-methoxy-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 541 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.33 (d, J=6.0 Hz, 3H); 1.67 (br.s, 4H);2.32 (s, 3H); 2.65-2.69 (m, 2H); 2.94-2.96 (m, 2H); 3.39-3.57 (m, 2H);3.63 (s, 3H); 3.67-3.69 (m, 2H); 4.09-4.12 (m, 1H); 4.55 (d, J=3.0 Hz,2H); 6.25 (d, J=6.0 Hz, 2H); 6.61-7.99 (m, 7H); 11.10 (m, 2H); 13.50 (s,1H).

Preparation(S)-2-(4-(1-(2-ethylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 525 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.20 (t, J=6.0 Hz, 3H); 1.33 (d, J=3.0 Hz,3H); 1.79 (br.s, 4H); 2.65-2.81 (m, 4H); 2.98-3.00 (m, 2H); 3.39-3.51(m, 4H); 3.63-3.69 (m, 2H); 4.08-4.15 (m, 1H); 4.55 (d, J=3.0 Hz, 2H);6.12 (d, J=6.0 Hz, 2H); 7.15-7.99 (m, 7H); 11.10 (m, 2H); 13.50 (s, 1H).

Preparation of(S)-2-(4-(1-(2,3-difluoro-5,6-dimethoxyphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 593 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (d, J=3.0 Hz, 3H); 1.67 (br.s, 4H);2.65-2.69 (m, 22.85-3.11 (m, 2H); 3.39-3.51 (m, 4H); 3.63-3.69 (m, 2H);3.75 (2 s, 6H); 3.98-4.05 (m, 1H); 4.55 (s, 2H); 6.20 (d, J=6.0 Hz, 2H);7.15-7.99 (m, 4H); 11.10 (m, 2H); 1150 (s, 1H).

Preparation of(S)-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 569 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (d, J=3.0 Hz, 3H); 1.67 (br.s, 4H);2.65-2.69 (m, 22.85-3.11 (m, 2H); 3.39-3.51 (m, 4H); 3.63-3.69 (m, 2H);3.98-4.05 (m, 1H); 4.55 (s, 2H); 6.20 (d, J=6.0 Hz, 2H); 7.15-7.99 (m,4H); 11.10 (m, 2H); 13.50 (s, 1H).

Preparation of(S)-2-(4-(1-(3,5-difluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 547 (M+1).

¹H NMR (300 MHz, DMSO-d₆): δ 1.23 (d, J=3.0 Hz, 3H); 1.67 (br.s, 4H);2.00 (m, 3H); 2.50 (s, 3H); 2.60-2.70 (m, 2H); 2.76-2.83 (m, 1H);2.86-3.07 (m, 3H); 3.62-3.64 (m, 2H); 4.02-4.20 (m, 1H); 4.53 (s, 2H);6.13 (d, J=6.0 Hz, 1H); 6.90-7.40 (m, 5H); 11.20 (2 br.s, 2H); 13.00 (s,1H).

Preparation of5,6-diamino-4-methyl-2-(2-(pyrrolidin-1-yl)ethyl)isoindoline-1,3-dione

To a solution of 4-amino-6-(methoxycarbonyl)-2-methyl-3-nitrobenzoicacid (380 mg, 1.0 mmol), HATU (114 mg, 1.0 mmol) and DIPEA (129 mg, 1.0mmol) in THF (20 mL) was added 2-(pyrrolidin-1-yl)ethanamine (114 mg,1.0 mmol) and stirred at RT for overnight. The reaction mixture wasevaporated in vacuo and the residue was triturated with MeOH (10 mL).The yellow precipitate was isolated by filtration and dried to affordthe title compound (300 mg) as a yellow solid.

The above residue was further treated with 10% Pd/C, H₂ in MeOH at RT toafford5,6-diamino-4-methyl-2-(2-(pyrrolidin-1-yl)ethyl)isoindoline-1,3-dione(quantitative) as a yellow solid. LCMS: 289 (M+1).

Preparation of(S)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(2-(pyrrolidin-1-yl)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 543 (M+1). Two isomers in 8:2 ratio and were not separable by HPLCand column chromatography.

Preparation of(S)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-morpholinoethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 545 (M+1).

Preparation of(S)-6-(2-morpholinoethyl)-2-(2-oxo-4-(1-(2,3,5-trifluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 567 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 1.37 (d, J=3.0 Hz, 3H);2.30-2.60 (m, 4H); 2.90-3.12 (m, 2H); 3.35 (br.s, 4H); 3.50-3.74 (m,4H); 4.10-4.25 (m, 1H); 4.56 (s, 2H); 6.16 (d, J=5.5 Hz, 1H); 6.94-7.03(m, 1H); 7.25-7.34 (m, 2H); 7.61-7.98 (m, 2H); 11.06-11.28 (m, 2H);13.10 (s, 1H).

Preparation of(S)-2-(4-(1-(2-methyl-5-(trifluoromethyl)phenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-morpholinoethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 595 (M+1).

Preparation of 1,5-Difluoro-2-methyl-3-nitrobenzene

To a stirred solution of 2,4-difluorotoluene (25.0 g, 195.3 mmol) inconc. H₂SO₄ (60 mL) was added fuming HNO₃ (30 mL) drop wise at the ratethat temperature was maintained between 40-50° C. over a period of 1.5h. The reaction mixture was stirred at 40° C. for an additional 1 h. Thereaction mixture was poured into ice-cold water (500 mL) and the solidprecipitated was filtered and washed with water (2×50 mL). The solidresidue was dissolved in EtOAc (200 mL), washed with aq. NaHCO₃ (2×200mL). The organic layer was dried over Na₂SO₄, filtered and evaporated invacuo to afford 1,5-difluoro-2-methyl-3-nitrobenzene (21.0 g, 62%) as alight brown liquid.

¹H MNR (CDCl₃, 300 MHz): δ 2.45 (s, 3H); 6.99 (dd, J=6.0 Hz, 1H); 8.00(dd, J=6.0 Hz, 1H).

Preparation of 3,5-difluoro-2-methylbenzenamine

To a suspension of 1,5-difluoro-2-methyl-3-nitrobenzene (21.0 g, 121.4mmol) and 10% Pd/C (2.0 g) was added MeOH (200 mL) carefully and theflask was evacuated. The reaction mixture was flushed with hydrogenunder balloon pressure and stirred at RT for 2 h. The reaction mixturewas filtered through Celite bed and evaporated in vacuo to afford3,5-difluoro-2-methylbenzenamine (18.0 g, 97%) as a dark yellow liquid.

¹H MNR (CDCl₃, 300 MHz): δ 2.25 (s, 3H); 3.49 (br.s, 2H); 6.57 (t, J=9.0Hz, 1H); 6.71 (t, J=9.0 Hz, 1H).

Preparation of 1,5-difluoro-3-iodo-2-methylbenzene

To cold solution of 6N aq. HCl (200 mL) was added3,5-difluoro-2-methylbenzenamine (11.0 g, 77.0 mmol) in portions andstirred for 10 min. The solution of aq. NaNO₂ (6.37 g in 50 mL of water)wadded drop wise at 0° C. for 20 min. and the resulting mixture wasstirred for an additional 30 min. The solution of KI (93.20 mmol) inwater was added drop wise at 0° C. and stirred for 1 h. The reactionmixture was extracted with ether (2×100 mL) and washed with aq. solutionof Na₂S₂O₃ (2×100 mL). The organic layer was washed with brine (50 mL),dried over Na₂SO₄, filtered and dried to afford1,5-difluoro-3-iodo-2-methylbenzene (9.0 g, 46%) as a brown liquid.

¹H MNR (CDCl₃, 300 MHz): δ 2.28 (s, 3H); 6.77 (dd, J=6.0 Hz, J=9.0 Hz,1H); 7.56 (dd, J=6.0 Hz, J=9.0 Hz, 1H).

Preparation of6-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)-2-(2-oxo-4-((S)-1-(2,3,5-trifluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 565 (M+1).

Preparation of(S)-6-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 565 (M+1).

Preparation of(′)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(methylamino)ethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

LCMS: 489 (M+1).

Chlorinated Compounds General Structure 1

5-Amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione:A suspension of5-amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (3.04 g,10 mmol) in HOAc (100 mL) was bubbled with Cl₂ gas for 5.5 h andevaporated to dryness. The residue was diluted with aqueous MeOH (25 mL,80%) and basified with aqueous NH₄OH solution (28%) resulting a solutionto which NaHSO₃ (10.4 g, 100 mmol) was added. The mixture was sonicatedfor 30 min and loaded on silica gel. Chromatography of the mixture withmixed solvent of CH₂Cl₂/MeOH/28% aqueous NH₄OH (20:10:1) afforded thetitle compound which is not pure, but was used for the next stepreaction directly without further purification.

5,6-Diamino-4-chloro-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione: Toa mixture of5-amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione(1.35 g, not pure) and 10% Pd/C (500 mg) was added 2-propanol (20 mL),HCl in dioxane (4 M, 0.1 mL) and then MeOH (230 mL). After it wasstirred under atmospheric hydrogen for 1.5 h, the reaction mixture wasfiltered over Celite. The filtrate was concentrated, diluted with 50%DCM in MeOH, basified with aqueous NH₄OH solution (28%) and evaporated.Chromatography of the mixture with mixed solvent of CH₂Cl₂/MeOH/28%aqueous NH₄OH (50:10:1) afforded the title compound (186 mg, 6% for 2steps). ¹H NMR (DMSO-d₆) δ 1.51 (m, 2H), 1.90 (m, 2H), 2.29 (m, 2H),2.81 (m, 2H), 3.80 (m, 1H), 5.61 (br s, 2H, NH₂), 5.93 (br s, 2H, NH₂),6.82 (s, 1H, ArH); ESI-MS m/z 309.4 (MH⁺).

4-Chloro-2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione:A solution of5,6-diamino-4-chloro-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione(62.0 mg, 0.2 mmol), 4-iodo-2-methoxynicotinic aldehyde (34.3 mg, 0.2mmol) and HOAc (1 mL) in MeOH was stirred at the room temperature for 14h, heated at 80° C. for 4.5 h, and concentrated to result a residuewhich was then mixed with HCl in dioxane (4 M, 10 mL) and H2O (0.8 mL)and heated for 1.7 h at 70° C. for 1.5 h. The reaction mixture wasevaporated, diluted with diluted with a mixed solvent of DCM/MeOH (1:5),basified with aqueous NH₄OH solution (28%) and evaporated.Chromatography of the residue with mixed solvent of CH₂Cl₂/MeOH/28%aqueous NH₄OH (40:10:1) afforded the title compound (70.2 mg, 78% for 2steps). ESI-MS m/z 446.5 (MH⁺).

4-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione:4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione(18 mg, 0.04 mmol), 1-methyl-2-thiophen-2-yl-ethylamine (8.5 mg, 0.06mmol) and Et₃N (0.2 mL, 1.43 mmol) in EtOH (1.0 mL) was heated at 80° C.for 17 h and then concentrated to result a residue which was subjectedto HPLC purification to furnish the title compound in TFA salt form(6.73 mg, 25%). ¹H NMR (DMSO-d₆) δ 1.36 (d, J=6 Hz, 3H, CH₃), 1.95 (m,2H), 2.52 (m, 2H), 2.74 (s, 3H, CH₃), 3.02-3.22 (4H), 3.45 (m, 2H), 4.08(m, 1H), 4.28 (m, 1H), 6.19 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.00 (m, 1H),7.29 (m, 1H), 7.39 (m, 1H), 8.09 (s, 1H), 11.01 (d, J=8 Hz, 1H), 11.35(d, J=6 Hz, 1H); ESI-MS m/z 551.3 (MH⁺).

8-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:4-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione(49 mg, 0.089 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) in HOAc(10 mL). After it was heated at 90° C. for 40 min, the reaction mixturewas cooled to 50° C. and diluted with a mixed solvent of MeOH:DCM (45mL/5 mL) and filtered. The filtrate was evaporated at 95° C. (the bathtemperature) under reduced pressure to dryness. The residue was dilutedwith a mixed solvent of DCM/MeOH (1:5) and basified with 28% aqueousNH₄OH solution and concentrated. Chromatography of the residual crudewith a mixed solvent of CH₃CN/CH₂Cl₂/MeOH/28% aqueous NH₄OH (63:10:37:1)followed by HPLC re-purification afforded the title compound in TFA saltform (6.2 mg, 11%). ¹H NMR (DMSO-d₆) δ 1.37 (d, J=6 Hz, 3H, CH₃),1.95-2.13 (4H), 2.52 (m, 2H), 2.80 (s, 3H, CH₃), 3.15 (m, 2H), 3.50-3.65(4H), 4.05 (m, 1H), 4.31 (m, 1H), 4.50 (br s, 2H), 6.18 (d, J=8 Hz, 1H),6.89 (m, 1H), 7.01 (m, 1H), 7.29 (m, 1H), 7.37 (m, 1H), 7.99 (s, 1H),9.60 (br s, 1H), 11.22 (d, J=6 Hz, 1H), 11.30 (d, J=6 Hz, 1H); ESI-MSm/z 537.3 (MH⁺).

General Structure 2

(S)-6-[1-(2-Ethanesulfonyl-ethyl)-piperidin-4-yl]-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one:¹H NMR (DMSO-d₆) δ 1.22 (t, J=6 Hz, 3H, CH₃), 1.34 (d, J=6 Hz, 3H, CH₃),1.70-1.82 (4H), 2.12 (m, 2H), 2.73 (m, 2H), 3.02 (m, 2H), 3.12-3.22(4H), 3.28 (m, 2H), 3.35 (s, 3H, CH₃), 4.05 (m, 2H), 4.49 (s, 2H), 6.16(d, J=6 Hz, 1H), 6.95 (m, 1H), 7.05 (s, 1H), 7.30-7.38 (2H), 7.66 (s,0.5H), 7.81 (s, 0.5H), 7.82 (s, 0.5H), 7.96 (s, 0.5H), 11.15 (br m, 1H,NH), 11.20 (br m, 1H, NH); ESI-MS m/z 609.7 (MH⁺).

The synthesis of(S)-6-[1-(2-Ethanesulfonyl-ethyl)-piperidin-4-yl]-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-onehas been accomplished by a general methodology outlined in: WO2008021369.

Example 2

SAR TABLE 1 Structure ALK IC50 IGF1R IC50 IRK IC50 TRKA IC50

+ − − NT

− NT NT NT

− NT NT NT

− NT NT NT

++ − − NT

++ + NT NT

++ NT NT NT

+ + NT NT

+ NT NT NT

− NT NT NT

− − NT NT

− − NT NT

− − − NT

− − + NT

− − − NT

++ + ++ NT

++ +++ NT NT

− + NT NT

+ ++ NT NT

− ++ NT NT

++ ++ − NT

++ ++ NT NT

+ + NT NT

− + NT NT

− ++ NT NT

− − NT NT

− − NT NT

− − NT NT

− − NT NT

− − − NT

++ + ++ NT

+ + NT NT

+ + NT NT

++ + NT NT

++ + NT NT

+ + ++ NT

++ + + NT

++ ++ + NT

NT NT NT NT

++ + ++ NT

++ − NT NT

++ − NT NT

+++ + +++ NT

+++ + NT NT

+++ ++ ++ NT

+++ + ++ NT

++ + NT NT

+++ + NT NT

++ + NT NT

++ + NT NT

++ − NT NT

+++ + NT NT

+++ − NT NT

+++ + NT NT

++ − NT NT

++ + NT NT

++ + NT NT

+++ ++ NT NT

+++ − − ++++

++++ ++ ++ ++++

+++ − + NT

+++ + ++ ++++

+++ − NT NT

+++ − NT NT

+++ − NT NT

+++ ++ NT NT

+++ − NT NT

+++ ++ NT NT

++++ + NT NT

++++ + NT NT

− + − ++

+++ +++ ++ +++

++++ ++ ++ ++++

++ ++ − NT

+++ + − NT

+++ ++ + NT

+++ ++ + NT

++++ ++ ++ NT

++ ++ − NT

++ ++ − NT

++ + + NT

++++ ++ + NT

+ ++ + NT

+++ + + NT

− − − NT

− − + NT

++++ + ++ NT

+++ + − NT

+ − − NT

++ + NT NT

+ − ++ NT

+ − ++ NT

− − NT NT

− − NT NT

+ + NT NT

+++ − + NT

++++ − + NT

+++ − + NT

++ − + NT

+++ − + NT

+++ − + NT

++++ − + NT

− + NT NT

++ + NT NT

+ +++ NT NT

++ − − NT ALK, IGF1R, IRK, TRKA IC50 (μM) +0.25-1 ++0.1-0.25 +++0.01-0.1++++<0.01 NT = not tested

Table I above presents the pharmacological data (IC₅₀ values) forspecific kinases showing the relative degree of potency of inhibition oftheir activity.

SAR TABLE 2 Enzy- Enzy- IC50 matic matic ALCL ALCL ALCL MM CON- ALKIGF1R (ALK) (ALK) (ALK) (IGF1R) TROL Structure IC50 IC50 JB6 Karpas299Uconn H929 W138

++++ ++ ++++ ++++ +++ + −

++++ ++ ++++ ++++ +++ + −

++++ − ++++ ++++ +++ + −

++++ − ++++ ++++ +++ + −

+++ − +++ +++ +++ + −

++++ +++ ++++ +++ +++ + −

++++ ++ +++ +++ +++ + −

++++ ++ +++ +++ +++ + −

+++ + +++ +++ +++ + −

+++ + +++ +++ ++ + − ALK, IGF1R IC50 (μM) +0.25-1 ++0.1-0.25 +++0.01-0.1++++<0.01 Cell lines IC50 +0.25-1 ++0.1-0.25 +++0.01-0.1 ++++<0.01

Table 2 above presents the pharmacological data (IC₅₀ values) forspecific kinases showing the relative degree of potency of inhibition oftheir cell-based activity.

All publications, patents and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsprovided herein that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed:
 1. A compound according to the formula (I) or astereoisomer, tautomer, or salt thereof:

wherein: R² and R³ are each independently hydrogen, lower alkyl, loweralkoxy, halogen, cyano, lower alkylamino, or di-lower alkylamino; W isO, S, or NR^(e), wherein R^(e) is selected from hydrogen and loweralkyl; or W represents bonding of two hydrogen atoms to a carbon atom,forming an optionally substituted methylene group:

wherein R^(f) is selected from hydrogen and lower alkyl; R⁴ is

wherein  R^(a) is optionally substituted aryl or heteroaryl;  R^(b) islower alkyl, trifluoromethyl, methoxymethyl, aminomethyl, di-loweralkylaminomethyl, or heterocyclylaminomethyl;  R^(c) is selected fromhydrogen, lower alkoxy, and lower alkyl;  R^(d) is selected fromhydrogen, and lower alkyl; and R¹ is independently selected fromoptionally substituted heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, heterocyclyloxyalkyl, heteroalkyl,heterocyclylaminoalkyl, aminoalkyl, lower alkylaminoalkyl, di-(loweralkyl)-aminoalkyl, aminocycloalkyl, alkylaminocycloalkyl, di-(loweralkyl)-aminocycloalkyl, and di-(lower alkyl)-aminocycloalkylalkyl,wherein the substituents are selected from hydrogen, lower alkyl,hydroxy, lower alkoxy, amino, amidino, carboxamido, sulfonamido,hydroxy, cyano, primary, secondary or tertiary amino, halo, azido, loweralkoxyalkyl, cyanoalkyl, azidoalkyl, haloalkyl, hydroxyalkyl,methanesulfonylalkyl, primary, secondary or tertiary amino-alkyl,optionally substituted aryl, heteroaryl, heteroalkyl, heterocyclyl,cycloalkyl, alkenyl, and alkynyl.
 2. The compound of claim 1, wherein R²and R³ are hydrogen or methyl.
 3. The compound of claim 1, wherein Wrepresents bonding of two hydrogen atoms to a carbon atom, formingmethylene.
 4. The compound of claim 1, wherein R^(a) is optionallysubstituted thienyl or phenyl wherein the optional substituents arealkyl, alkoxy or halo.
 5. The compound of claim 1, wherein R^(a) isoptionally substituted thienyl or phenyl wherein the optionalsubstituents are methyl, methoxy or fluoro.
 6. The compound of claim 1,wherein R^(a) is 2-thienyl, phenyl, 3-methyl-2-thienyl, 2-methylphenyl,5-fluoro-2-methylphenyl, 5-fluoro-2-methoxyphenyl, 2,3,5-trifluorophenylor 2,3,5,6-tetrafluorophenyl.
 7. The compound of claim 1, wherein R^(c)and R^(d) are hydrogen.
 8. The compound of claim 1, wherein R^(b) isalkyl.
 9. The compound of claim 1, wherein R^(b) is methyl.
 10. Thecompound according to claim 1, wherein R¹ is selected from the groupconsisting of:

wherein: R¹³ is selected from hydrogen, lower alkyl, heteroalkyl,heterocyclyl, cycloalkyl, and heterocycloalkyl; R¹⁴ is selected fromhydrogen, hydroxy, lower alkoxy, di-(lower alkyl)amino, lower alkyl,heteroalkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, loweralkoxyalkyl, cyanoalkyl, azidoalkyl, nitroalkyl, ketoalkyl,methanesulfonylalkyl, aminoalkyl, lower alkylaminoalkyl, di-(loweralkyl)aminoalkyl, optionally substituted aryl, heteroaryl, arylalkyl,and heteroarylalkyl; R¹⁵ is selected from hydrogen, amino, loweralkylamino, di-(lower alkyl)amino, hydroxy, lower alkoxy, heteroalkyl,lower alkoxyalkyl, aminoalkyl, lower alkylaminoalkyl, and di-(loweralkyl)aminoalkyl; a is an integer from 0 to 4; and t, u, v areindependent integers from 0 to
 5. 11. The compound according to claim 1,wherein R¹ is selected from the group consisting of:


12. The compound according to claim 1, wherein the R¹ methylene chainbetween the connection and the heteroatom is optionally substituted byone or more hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, loweralkoxy, carboxamido or sulfonamido.
 13. The compound according to claim1, wherein the R¹ methylene groups are optionally substituted by aheteroatom selected from O and S, NR***, S═O, or S(═O)₂, wherein R*** isselected from hydrogen, hydroxy, lower alkyl, lower alkoxy, heteroalkyl,hydroxyalkyl, aminoalkyl, lower alkylaminoalkyl and di-(loweralkyl)aminoalkyl.
 14. The compound according to claim 1, wherein the R¹ring is optionally substituted by a lower alkyl or heteroalkyl group.15. The compound according to claim 1 having the following formula (Ia):


16. A compound according to claim 1, wherein the compound is selectedfrom the group consisting of:


17. A compound of any one of claims 1 to 16 which is a selective Alkinhibitor.
 18. A pharmaceutical composition comprising a compoundaccording to any one of claims 1 to 16 and one or more pharmaceuticallyacceptable diluents, excipients or carriers.
 19. A method of modulatinga tyrosine kinase activity comprising the step of contacting thetyrosine kinase with an amount of a compound according to any one ofclaims 1 to 16 effective to modulate the tyrosine kinase activity. 20.The method of claim 19, wherein said tyrisone kinase is selected fromthe group consisting of Alk, Axl, CSFR, DDR1, DDR2, EphB4, EphA2, EGFR,Flt-1, Flt3, Flt4, FGFR1, FGFR2, FGFR3, FGFR4, HER2, HER3, HER4, IR,IGF1R, IRR, Kit, KDR/Flk-1, Met, Mer, PDGFR.alpha., PDGFR.beta., Ret,Ros, Ron, Tie1, Tie2, TrkA, TrkB and TrkC.
 21. The method of claim 20,wherein the tyrosine kinase is Alk, Axl, Ret, Ros, TrkA, TrkB or TrkC.22. The method of claim 20, wherein the tyrosine kinase is Alk.
 23. Amethod of treating a condition or disorder related to tyrosine kinaseactivity comprising administering to a subject a compound according toany one of claims 1 to 16 wherein said condition or disorder is selectedfrom the group consisting of ALK-positive anaplastic large celllymphoma, an inflammatory myofibroblastic tumor, diffuse large B-cellnon-Hodgkin lymphoma, non-small cell lung cancer, esophageal carcinoma,breast cancer, neuroblastoma and glioblastoma.
 24. The method of claim23, wherein the tyrosine kinase activity is Alk activity.
 25. A methodof inhibiting a tyrosine kinase activity comprising contacting thetyrosine kinase with a compound according to any one of claims 1 to 16.26. The method of claim 25, wherein the tyrosine kinase activity is Alkactivity.